Protein kinase C inhibitors and methods of their use

ABSTRACT

PKC inhibitors are disclosed. The PKC inhibitors are useful for treating PKC associated diseases, including certain cancers. The PKC inhibitors have improved efficacy at lower dosage amounts to achieve tumor regression, improved potency, PK profile, absorption, gastrointestinal tolerance and kinase selectivity.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/830,769 filed Dec. 4, 2017, which is a continuation of U.S.application Ser. No. 15/237,880 filed Aug. 16, 2016, now U.S. Pat. No.9,845,309, which is a continuation of U.S. application Ser. No.14/818,778 filed Aug. 5, 2015, now U.S. Pat. No. 9,452,998, which claimspriority to U.S. Ser. No. 62/033,676, filed Aug. 6, 2014. The entirecontents of all of these applications are incorporated herein byreference in their entireties.

FIELD OF THE INVENTION

The present invention relates to new compounds and their tautomers andstereoisomers, and pharmaceutically acceptable salts, esters,metabolites or prodrugs thereof, compositions of the new compoundstogether with pharmaceutically acceptable carriers, and uses of the newcompounds, either alone or in combination with at least one additionaltherapeutic agent, in the prophylaxis or treatment of cancer.

BACKGROUND

Uveal melanoma is the most common primary intraocular malignant tumor inadults. Certain protein kinase inhibitors are described in InternationalPubl. Nos. WO 02/38561 and WO 2008/106692. One protein kinase C (PKC)inhibitor, sotrastaurin, has been shown to have activity against certainPKC isototypes and has only recently been shown to selectively inhibitthe growth of uveal melanoma cells harboring GNAQ mutations by targetingPKC/ERK1/2 and PKC/NF-κB pathways (see X. Wu, et al in Mol. CancerTher., Vol. 11, pages 1905-1914, 2012). A clinical trial studying theuse of sotrastaurin to treat patients having uveal melanoma is inprogress. However, there still remains a unmet need to provide nextgeneration PKC inhibitors for treating uveal melanoma that have improvedefficacy at lower dosage amounts to achieve tumor regression, improvedpotency, hERG activity, absorption, gastrointestinal tolerance andkinase selectivity.

Diffuse large B-cell lymphoma (DLBCL) represents the most common subtypeof malignant lymphoma and is heterogeneous with respect to morphology,biology and clinical presentation. The PKC inhibitor, sotrastaurin(AEB071), has been shown to selectively inhibit growth of CD79-mutantDLBCL cells (see T. Naylor, et al in Cancer Res., Vol. 71(7), 2643-2653,2011). In addition the study suggested that sotrastaurin showedsignificant synergy when combined with the mTor inhibitor everolimus(Afinitor™). A clinical trial studying the use of sotrastaurin to treatpatients having DLBCL harboring the CD79 mutation is in progress.However, there still remains a unmet need to provide next generation PKCinhibitors for treating DLBCL that have improved efficacy at lowerdosage amounts to achieve tumor regression, improved potency, PKprofile, absorption, gastrointestinal tolerance and kinase selectivity.

SUMMARY

New compounds, their tautomers, stereoisomers, or pharmaceuticallyacceptable salts thereof or esters having a solubility enhancingmoieties or prodrugs thereof are provided of the formula (I):

-   -   wherein:    -   R¹ is optionally substituted 6-10 membered aryl or 5-10 membered        heteroaryl having 1 to 4 heteroatoms each independently selected        from the group consisting of: O, N and S, said heteroaryl or        aryl each being optionally substituted with 1 to 3 substituents        each independently selected from the group consisting of: H, ²H,        halo, C₂₋₃ alkynyl, C₂₋₃ alkenyl, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy,        C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl, CONH₂,        CONHC₁₋₃ alkyl, CONHC₆₋₁₀ aryl, SO₂NH₂, SO₂NHC₁₋₃ alkyl,        SO₂NHC₆₋₁₀ aryl and 4-7 membered heterocyclyl having 1 to 3        heteroatoms selected from N, O and S, said heterocyclyl        optionally substituted with 1 to 3 substituents each        independently selected from the group consisting of: H, ²H,        halo, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃        haloalkoxy;    -   R², R³ and R⁴ are each independently H, ²H, halo, hydroxy (—OH),        C₁₋₃ alkoxy, C₁₋₃ haloalkyl or C₁₋₃ alkyl, optional substituted        with one to two of hydroxyl, halo and C₁₋₃ haloalkoxy;    -   R⁵ is H, ²H, CH₃, CH₂F, CHF₂, CF₃, CH₂OH, C₁₋₃ alkyl, CH₂—O—C₁₋₃        alkyl or CH₂—O—C₁₋₃ haloalkyl, said C₁₋₃ alkyl optionally        substituted with H, F, OH, C₁₋₃ alkoxy and C₁₋₃ haloalkoxy;    -   R^(5a) and R^(5b) are each independently H, ²H, C₁₋₃ alkyl, said        C₁₋₃ alkyl optionally substituted with F, OH, or C₁₋₃ alkoxy, or        R^(5a) and R^(5b) are joined together forming a methylene or        ethylene bridging group; and    -   R^(5c) and R^(5d) are each independently H, ²H, F, —OH, C₁₋₃        alkyl, said C₁₋₃ alkyl optionally substituted with F, OH, or        C₁₋₃ alkoxy, or R^(5c) and R^(5d) are joined together forming a        methylene, ethylene or —CH₂—O— bridging group.

In a separate embodiment, compounds, their tautomers, stereoisomers orpharmaceutically acceptable salts thereof or esters having a solubilityenhancing moieties or prodrugs thereof are provided of the formula (Ia):

-   -   wherein:    -   R¹ is optionally substituted C₆₋₁₀ aryl, said aryl being        optionally substituted with one to three substituents each        independently selected from the group consisting of: H, ²H,        halo, C₂₋₃ alkynyl, C₂₋₃ alkenyl, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy,        C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl, CONH₂,        CONHC₁₋₃ alkyl, CONHC₆₋₁₀ aryl, SONH₂, SONHC₁₋₃ alkyl, SONHC₆₋₁₀        aryl and 4-7 membered heterocyclyl having 1 to 3 heteroatoms        selected from N, O and S, said heterocyclyl optionally        substituted with 1 to 3 substituents each independently selected        from the group consisting of: H, ²H, halo, CN, C₁₋₃ alkyl, C₁₋₃        alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ haloalkoxy;    -   R², R³ and R⁴ are each independently H, ²H, halo, hydroxy (—OH),        C₁₋₃ alkoxy, C₁₋₃ haloalkyl or C₁₋₃ alkyl, optional substituted        with one to two of hydroxy, halo and C₁₋₃ haloalkoxy;    -   R⁵ is —H, ²H, CH₃, CH₂F, CHF₂, CF₃, CH₂OH, C₁₋₃ alkyl,        CH₂—O—C₁₋₃ alkyl or CH₂—O—C₁₋₃ haloalkyl, said C₁₋₃ alkyl        optionally substituted with H, F, OH, C₁₋₃ alkoxy and C₁₋₃        haloalkoxy;    -   R^(5a) and R^(5b) are each independently H, ²H, C₁₋₃ alkyl, or        R^(5a) and R^(5b) are joined together forming a methylene or        ethylene bridging group; and    -   R^(5c) and R^(5d) are each independently H, F, C₁₋₃ alkyl, or        C₁₋₃ alkoxy or R^(5c) and R^(5d) are joined together forming a        methylene, ethylene or —CH₂—O— bridging group.

In a separate embodiment, compounds, their tautomers, stereoisomers, orpharmaceutically acceptable salts thereof or esters having a solubilityenhancing moieties or prodrugs thereof are provided of the formula (II):

wherein:

-   X is N or CR;    -   R, R², R³ and R⁴ are each independently H, ²H, halo, hydroxy        (—OH), C₁₋₃ alkoxy, C₁₋₃ haloalkyl or C₁₋₃ alkyl, optionally        substituted with one to two of hydroxy, halo and C₁₋₃        haloalkoxy;    -   R⁵ is —H, ²H, CH₃, CH₂F, CHF₂, CF₃, CH₂OH, C₁₋₃ alkyl,        CH₂—O—C₁₋₃ alkyl or CH₂—O—C₁₋₃ haloalkyl, said C₁₋₃ alkyl        optionally substituted with H, F, OH, C₁₋₃ alkoxy and C₁₋₃        haloalkoxy;    -   R^(5a) and R^(5b) are each independently H, ²H, C₁₋₃ alkyl, said        C₁₋₃ alkyl optionally substituted with H, F, OH, C₁₋₃ alkoxy and        C₁₋₃ haloalkoxy or R^(5a) and R^(5b) are joined together forming        a methylene or ethylene bridging group;    -   R^(5c) and R^(5d) are each independently H, ²H, F, C₁₋₃ alkyl,        or C₁₋₃ alkoxy or R^(5c) and R^(5d) are joined together forming        a methylene, ethylene or —CH₂—O— bridging group; and    -   R⁶, R⁷, R⁸ and R⁹ are each independently selected from H, ²H,        halo, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, C₃₋₇        cycloalkyl and 4-7 membered heterocyclyl, each optionally        substituted with 1 to 3 substituents selected from H, halo,        hydroxyl, C₂₋₃ alkynyl, C₂₋₃ alkenyl, CN, C₁₋₃ alkyl, C₁₋₃        alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy and C₃₋₇ cycloalkyl; or    -   wherein R⁶ and R⁸ optionally form a partially saturated        carbobicyclic ring or heterobicyclic ring with the heteroaryl        ring, said carbobicyclic ring or heterobicyclic ring optionally        substituted with 1 to 3 groups selected from: H, ²H, halo, C₁₋₃        haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl and 4-7        membered heterocyclyl having 1 to 3 heteroatoms selected from N,        O and S.

In a separate embodiment, compounds, their tautomers, stereoisomers orpharmaceutically acceptable salts thereof or esters having a solubilityenhancing moieties or prodrugs thereof are provided of the formula(III):

-   -   wherein:    -   R¹ is optionally substituted 6-10 membered aryl or 5-10 membered        heteroaryl having 1 to 4 heteroatoms each independently selected        from the group consisting of: O, N and S, said heteroaryl or        aryl each being optionally substituted with 1 to 3 substituents        each independently selected from the group consisting of: H, ²H,        halo, C₂₋₃ alkynyl, C₂₋₃ alkenyl, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy,        C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl, CONH₂,        CONHC₁₋₃ alkyl, CONHC₆₋₁₀ aryl, SO₂NH₂, SO₂NHC₁₋₃ alkyl,        SO₂NHC₆₋₁₀ aryl and 4-7 membered heterocyclyl having 1 to 3        heteroatoms selected from N, O and S, said heterocyclyl        optionally substituted with 1 to 3 substituents each        independently selected from the group consisting of: H, ²H,        halo, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃        haloalkoxy;    -   R², R³ and R⁴ are each independently H, ²H, halo, hydroxy (—OH),        C₁₋₃ alkoxy, C₁₋₃ haloalkyl or C₁₋₃ alkyl, each further        optionally substituted with one to two of hydroxy, halo and C₁₋₃        haloalkoxy; and    -   R⁹ is independently H or 4-7 membered heterocyclyl or        heterobicyclyl having 1 to 3 heteroatoms selected from N, O and        S, SO, SO₂, said heterocycyl or heterobicylyl substituted with 1        to 4 substituents each independently selected from the group        consisting of: H, ²H, amino (NH₂), halo, CN, C₁₋₃ alkyl, C₁₋₃        alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl, C₂₋₃        alkynyl, C₂₋₃ alkenyl, COOC₁₋₃ alkyl, CONH₂, CONHC₁₋₃ alkyl,        CONHC₆₋₁₀ aryl, SO₂NH₂, SO₂NHC₁₋₃ alkyl, SO₂NHC₆₋₁₀ aryl        —O—(CH₂)-heterocyclyl (n=1-3), CO NH₂, said C₁₋₃ alkyl or        —O—(CH₂)-heterocyclyl, said heterocylyl having 1 to 3        heteroatoms selected from N, O and S, SO, SO₂ each optionally        substituted with 1 to 4 substituents selected from H, NH₂, OH,        halo, C₁₋₃ alkoxy and C₁₋₃ haloalkoxy.

In other aspects, the present invention provides a pharmaceuticalcomposition comprising: a compound of formula (I), (Ia), (II) or (III)or a pharmaceutically acceptable salt thereof and at least onepharmaceutically acceptable carrier.

In other aspects, the present invention provides a method for treatingprotein kinase C related disorders, specifically protein kinase Cisoforms alpha and/or theta (PKCα/θ)), related disorders in a human oranimal subject in recognized need of such treatment comprisingadministering to said subject an amount of a compound of formula (I),(II) or (III) or a pharmaceutically acceptable salt thereof effective toinhibit the PKCα/θ related activity in the subject.

The compounds of the invention are useful in the treatment of cancers,including for example melanoma, uveal melanoma, lymphoma, diffuse largeB-cell lymphoma (DLBCL) and ibrutinib resistant cancers.

The compounds of the invention are also for treating immune relateddisorders, including but not limited to autoimmune diseases, allergicreaction and tissue transplant rejection, in a human or animal subjectin recognized need of such treatment comprising administering to saidsubject an amount of a compound of formula (I), (Ia), (II) or (III) or apharmaceutically acceptable salt thereof effective to reduce or preventtumor growth in the subject.

The invention further provides compositions, methods of use, and methodsof manufacture of a compound of formula (I), (Ia), (II) or (III), or apharmaceutically acceptable salt thereof as described in the detaileddescription of the invention.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 summarizes that Example 2 decreases tumor proliferation in a 92.1uveal melanoma xenografts in a dose dependent manner, as compared tosotrastaurin.

FIG. 2 summarizes that Example 9 decreases tumor proliferation in a 92.1uveal melanoma xenografts in a dose dependent manner, as compared tosotrastaurin.

FIG. 3 depicts the reduction in tumor volume over timepost-administration of Example 10 and Example 9, as compared to vehicle.

DETAILED DESCRIPTION

The phrase “alkyl” refers to alkyl groups that do not containheteroatoms. Thus the phrase includes straight chain alkyl groups suchas methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl and the like. The phrase also includes branchedchain isomers of straight chain alkyl groups, including but not limitedto, the following which are provided by way of example: —CH(CH₃)₂,—CH(CH₃)(CH₂CH₃), —CH(CH₂CH₃)₂, —C(CH₃)₃, —C(CH₂CH₃)₃, —CH₂CH(CH₃)₂,—CH₂ CH(CH₃)(CH₂CH₃), —CH₂CH(CH₂CH₃)₂, —CH₂C(CH₃)₃, —CH₂C(CH₂CH₃)₃,—CH(CH₃)—CH(CH₃)(CH₂CH₃), —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH(CH₃)(CH₂CH₃),—CH₂CH₂CH(CH₂CH₃)₂, —CH₂CH₂C(CH₃)₃, —CH₂CH₂C(CH₂CH₃)₃,—CH(CH₃)CH₂—CH(CH₃)₂, —CH(CH₃)CH(CH₃)CH(CH₃)₂,—CH(CH₂CH₃)CH(CH₃)CH(CH₃)(CH₂CH₃), and others. The phrase also includescyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted withstraight and branched chain alkyl groups as defined above. Thus the term“C₁₋₁₂ alkyl group” includes primary alkyl groups, secondary alkylgroups, and tertiary alkyl groups. Alkyl groups include straight andbranched chain alkyl groups and cyclic alkyl groups having 1 to 12carbon atoms.

As used herein, “C₁₋₆ alkyl” includes both substituted or unsubstitutedstraight or branched chain alkyl groups having from 1 to 6 carbon atoms.Representative C₁₋₆ alkyl groups include, for example, methyl, ethyl,propyl, isopropyl, n-butyl, tert-butyl, neopentyl, tri-fluoromethyl,pentafluoroethyl and the like. C₁₋₆ alkyl groups may be substituted,such as with halo, hydroxy, amino, nitro and/or cyano groups, and thelike. Representative C₁₋₃ haloalkyl and C₁₋₃ hydroxyalkyl includechloromethyl, tri chloromethyl, trifluoromethyl, fluoromethyl,fluoroethyl, chloroethyl, hydroxymethyl, hydroxyethyl, and the like.Other suitable substituted C₁₋₃ alkyl moieties include, for example,aralkyl, aminoalkyl, aminoaralkyl, carbonylaminoalkyl,alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,aralkylcarbonylaminoalkyl, aminoalkoxyalkyl and arylaminoalkyl.

As used herein, “C₁₋₆ alkoxy” as used herein refers to the radical RO—,wherein R is C₁₋₆ alkyl. Representative examples of C₁₋₆ alkoxy groupsinclude methoxy, ethoxy, t-butoxy, trifluoromethoxy and the like.

As used herein, the term “halogen” or “halo” refers to chloro, bromo,fluoro and iodo groups. “Haloalkyl” refers to a C₁₋₃ alkyl radicalsubstituted with one or more halogen atoms. The term “haloalkoxy” refersto a C₁₋₃ alkoxy radical substituted with one or more halogen atoms.Hydroxy refers to the group —OH.

“Amino” refers herein to the group —NH₂. The term “C₁₋₃ alkylamino”refers herein to the group —NRR′ where R and R′ are each independentlyselected from hydrogen or a C₁₋₃ alkyl. The term “arylamino” refersherein to the group —NRR′ where R is C₆₋₁₀ aryl, including phenyl, andR′ is hydrogen, a C₁₋₃ alkyl, or C₆₋₁₀ aryl, including phenyl. The term“aralkylamino” refers herein to the group —NRR′ where R is a aralkyl andR′ is hydrogen, a C₁₋₃ alkyl, an aryl, including phenyl, or a aralkyl.

The term “alkoxyalkyl” refers to the group -alk₁-O-alk₂ where alk₁ isC₁₋₃ alkyl, and alk₂ is C₁₋₃ alkyl. The term “aryloxyalkyl” refers tothe group —C₁₋₃ alkyl-O-aryl, wherein aryl is C₆₋₁₀ aryl, includingphenyl. The term “aralkoxyalkyl” refers to the group-alkylenyl-O-aralkyl, where aralkyl is a lower aralkyl.

The term “aminocarbonyl” refers herein to the group —C(O)—NH₂.“Substituted aminocarbonyl” refers herein to the group —CO—NHR— or—C(O)—NRR′ where R is C₁₋₃ alkyl or C₆₋₁₀ aryl and R′ is hydrogen, C₁₋₃alkyl or C₆₋₁₀ aryl. In some embodiments, R and R′, together with the Natom attached to them may be taken together to form a“heterocycloalkylcarbonyl” group. The term “carboxyamido” also refers tothe group —CONH₂. The term “substituted carboxyamide” refers herein tothe group —CO—NHR— or —CO—NRR′ where R is C₁₋₃ alkyl, C₆₋₁₀ aryl or and4-7 membered heterocyclyl having 1 to 3 heteroatoms selected from N, Oand S, said heterocyclyl optionally substituted with 1 to 3 substituentseach independently selected from the group consisting of: H, ²H, halo,CN, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ haloalkoxy and R′is hydrogen, C₁₋₃ alkyl, C₆₋₁₀ aryl or and 4-7 membered heterocyclylhaving 1 to 3 heteroatoms selected from N, O and S, said heterocyclyloptionally substituted with 1 to 3 substituents each independentlyselected from the group consisting of: H, ²H, halo, CN, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ haloalkoxy. The term“arylaminocarbonyl” refers herein to the group —C(O)—NRR′ where R is anaryl and R′ is hydrogen, C₁₋₃ alkyl or aryl. The term“aralkylaminocarbonyl” refers herein to the group —C(O)—NRR′ where R isaralkyl and R′ is hydrogen, C₁₋₃ alkyl, aryl, phenyl or aralkyl.

The term “aminosulfonyl” refers herein to the group —SO₂—NH₂.“Substituted aminosulfonyl” refers herein to the group —SO₂—NHR— or—SO₂—NRR′ where R is C₁₋₃ alkyl or C₆₋₁₀ aryl and R′ is hydrogen or aC₁₋₃ alkyl or C₆₋₁₀ aryl. The term “sulfonamido” refers to the group—SONH₂. The term “substituted sulfonamide” refers herein to the group—SO—NHR— or —SO—NRR′ where R is C₁₋₃ alkyl, C₆₋₁₀ aryl or and 4-7membered heterocyclyl having 1 to 3 heteroatoms selected from N, O andS, said heterocyclyl optionally substituted with 1 to 3 substituentseach independently selected from the group consisting of: H, ²H, halo,CN, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ haloalkoxy and R′is hydrogen or a C₁₋₃ alkyl, C₆₋₁₀ aryl or and 4-7 membered heterocyclylhaving 1 to 3 heteroatoms selected from N, O and S, said heterocyclyloptionally substituted with 1 to 3 substituents each independentlyselected from the group consisting of: H, ²H, halo, CN, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ haloalkoxy. The term“aralkylaminosulfonlyaryl” refers herein to the group-aryl-S(O)₂—NH-aralkyl.

The term “carbonyl” refers to the divalent group —C(O)—. “Carboxy”refers to —C(═O)—OH. “Alkoxycarbonyl” refers to ester —C(═O)—OR whereinR is C₁₋₃ alkyl. “Cycloalkyloxycarbonyl” refers to —C(═O)—OR wherein Ris cycloalkyl. The term “aryloxycarbonyl” refers to —C(═O)—OR wherein Ris aryl. The term “heterocyclyloxycarbonyl” refers to —C(═O)—OR whereinR is heterocyclyl.

The term “aralkoxycarbonyl” refers herein to the group —(C═O)—O-aralkyl,where the aralkyl is araC₁₋₃ alkyl.

The term “sulfonyl” refers herein to the group —SO₂—. The term“sulfanyl” refers herein to the group —S—. “Alkylsulfonyl” refers to asubstituted sulfonyl of the structure —SO₂R— in which R is C₁₋₃ alkyl.“Alkylsulfanyl” refers to a substituted sulfanyl of the structure —SR—in which R is C₁₋₃ alkyl. Thus, typical alkylsulfonyl andloweralkylsulfanyl groups employed in compounds of the present inventioninclude, for example, methylsulfonyl and methylsulfanyl (i.e., where Ris methyl), ethylsulfonyl and ethylsulfanyl (i.e., where R is ethyl),propylsulfonyl and propylsulfanyl (i.e., where R is propyl), and thelike. The term “arylsulfonyl” refers herein to the group —SOO₂-aryl. Theterm “aralkylsulfonyl” refers herein to the group —SO₂-aralkyl, in whichthe aralkyl is araC₁₋₃ alkyl. The term “sulfonamido” refers herein to—SO₂NH₂.

Alternatively, the term “amido” refers to —C(═O)NH₂ and “carbonylamino”refers to the divalent group —NH—(C═O)— in which the hydrogen atom ofthe amide nitrogen of the carbonylamino group can be replaced a C₁₋₃alkyl, C₆₋₁₀ aryl, aralkyl or and 4-7 membered heterocyclyl having 1 to3 heteroatoms selected from N, O and S, said heterocyclyl optionallysubstituted one or two substituents each independently selected from thegroup consisting of: H, ²H, halo, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃haloalkyl, and C₁₋₃ haloalkoxy. Such groups include moieties such ascarbamate esters (—NH—C(O)—O—R) and amides —NH—C(O)—R, where R is astraight or branched chain C₁₋₃ alkyl, C₃₋₈ cycloalkyl, or C₆₋₁₀ aryl,including phenyl, aralkyl or and 4-7 membered heterocyclyl having 1 to 3heteroatoms selected from N, O and S, said heterocyclyl optionallysubstituted with 1 to 3 substituents each independently selected fromthe group consisting of: H, ²H, halo, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃haloalkyl, and C₁₋₃ haloalkoxy.

The term “C₃₋₈ cycloalkyl” refers to a mono- or polycyclic, heterocyclicor carbocyclic C₃₋₈ alkyl substituent. Typical cycloalkyl substituentshave from 3 to 8 backbone (i.e., ring) atoms in which each backbone atomis either carbon or a heteroatom. The term “heterocycloalkyl” refersherein to cycloalkyl substituents that have from 1 to 5, and moretypically from 1 to 4 heteroatoms in the ring structure. Suitableheteroatoms employed in compounds of the present invention are nitrogen,oxygen, and sulfur. Representative heterocycloalkyl moieties include,for example, morpholino, piperazinyl, piperidinyl and the like.Carbocycloalkyl groups are cycloalkyl groups in which all ring atoms arecarbon. When used in connection with cycloalkyl substituents, the term“polycyclic” refers herein to fused and non-fused alkyl cyclicstructures. The term “carbobicyclic or carbobicyclyl” refers to asaturated, orpartially unsaturated carbocyclic ring fused to anothercarbocyclic ring, aryl ring, heterocyclic ring or heteroaryl ring. Thecycloalkyl group is unsubstituted or substituted.

The term “substituted heterocycle” or “heterocyclic group” or“heterocyclyl”, as used herein, refers to any 3- or 4-membered ringcontaining a heteroatom selected from nitrogen, oxygen, and sulfur or a5-, 6- or 7-membered ring containing from one to three heteroatomsselected from the group consisting of nitrogen, oxygen, or sulfur;wherein the 5-membered ring has 0-1 double bonds and the 6- and7-membered rings have 0-1 double bonds or fused rings having 0-2 doublebonds; wherein the nitrogen and sulfur atom maybe optionally oxidized;wherein the nitrogen and sulfur heteroatoms may be optionallyquarternized; and including any bicyclic group in which any of the aboveheterocyclic rings is fused to a benzene ring or another 5- or6-membered heterocyclic ring independently defined above and is referredto as a heterobicyclic ring or a heterobicyclyl group. The heterocylylgroup is unsubstituted or substituted with 1 to 3 substituents eachindependently selected from the group consisting of: H, ²H, halo, CN,C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ haloalkoxy.

The term “heterocycle” thus includes rings in which nitrogen is theheteroatom as well as partially and fully-saturated rings. Exemplaryheterocycles include but are not limited to, for example: piperidinyl,piperazinyl, 1,2-oxazinane, 2-oxopiperazinyl, 2-oxopiperidinyl, N-methylpiperazinyl, and morpholinyl, each optionally substituted.

Heterocyclic moieties can be unsubstituted or monosubstituted ordisubstituted with various substituents independently selected fromhydroxy, halo, oxo (C═O), alkylimino (RN═, wherein R is a C₁₋₃ alkyl orC₁₋₃ alkoxy group), amino, C₁₋₃ alkylamino, C₁₋₃ dialkylamino,acylaminoalkyl, C₁₋₃ alkoxy, C₁₋₃ alkyl, cycloalkyl or C₁₋₃ haloalkyl.

The heterocyclic groups (heterocyclyl) may be attached at variouspositions as will be apparent to those having skill in the organic andmedicinal chemistry arts in conjunction with the disclosure herein.Representative examples of heterocyclyl, heterobicyclyl and substitutedheterocyclyl groups used in accordance with the invention are listedbelow:

The term “C₆₋₁₀ aryl” refers to optionally substituted monocyclic andpolycyclic aromatic groups having from 6 to 10 or 3 to 14 backbonecarbon or hetero atoms, and includes both carbocyclic aryl groups andheterocyclic aryl groups. Carbocyclic aryl groups are C₆₋₁₀ aryl groupsin which all ring atoms in the aromatic ring are carbon. Exemplary C₆₋₁₀aryl moieties employed as substituents in compounds of the presentinvention include phenyl, naphthyl, isonaphthyl and the like.

“Aralkyl” refers to a C₁₋₃ alkyl or C₁₋₆ alkyl group substituted with anC₆₋₁₀ aryl group. Typically, aralkyl groups employed in compounds of thepresent invention have from 1 to 6 carbon atoms incorporated within thealkyl portion of the aralkyl group. Suitable aralkyl groups employed incompounds of the present invention include, for example, benzyl,picolyl, and the like.

The term “heteroaryl” refers to 5-10 membered carbocyclic ring system,including fused ring systems, having 1 to 4 heteroatoms eachindependently selected from the group consisting of: O, N and S. Saidheteroaryl may be optionally substituted with one or two substituents.The term “heteroaryl” also refers herein to C₆₋₁₀ aryl groups havingfrom 1 to 4 heteroatoms as ring atoms in an aromatic ring with theremainder of the ring atoms being carbon atoms. Exemplary substituentsinclude, but are not limited to: halo, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl, and 4-7 memberedheterocyclyl having 1 or 2 heteroatoms selected from N, O and S, saidheterocyclyl optionally substituted with 1 to 3 substituents eachindependently selected from the group consisting of: halo, CN, C₁₋₃alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ haloalkoxy Representativeheteroaryl groups include, for example, those shown below.Representative heteroaryls include, for example, imidazolyl, pyridinyl(also referred to aspyridyl), pyrazinyl, azetidinyl, thiazolyl,triazolyl, benzimidazolyl, benzothiazolyl, thiazolyl, thiazolidinyl,isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl,azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl, oxazolyl,oxazolidinyl, isoxazolyl, isoazolidinyl, benzimidazolyl, benzothiazolyl,benzoxazolyl, furyl, thienyl, triazolyl, benzothienyl diazapinyl,pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,imidazoyl, imidazolinyl, imidazolidinyl and benzoxazolyl. The heteroarylis unsubstituted or substituted with 1 to 3 substituents eachindependently selected from the group consisting of: H, ²H, halo, C₂₋₃alkynyl, C₂₋₃ alkenyl, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃haloalkoxy, C₃₋₇ cycloalkyl, CONH₂, CONHC₁₋₃ alkyl, CONHC₆₋₁₀ aryl,SO₂NH₂, SO₂NHC₁₋₃ alkyl, SO₂NHC₆₋₁₀ aryl and 4-7 membered heterocyclylhaving 1 to 3 heteroatoms selected from N, O and S, said heterocyclyloptionally substituted one or two substituents each independentlyselected from the group consisting of: H, ²H, halo, CN, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ haloalkoxy.

The heteroaryl groups can be further substituted and may be attached atvarious positions as will be apparent to those having skill in theorganic and medicinal chemistry arts in conjunction with the disclosureherein. Representative examples of heteroaryl and substituted heteroarylgroups used in accordance with the invention are listed below:

“Optionally substituted” or “substituted” refers to the replacement ofone or more hydrogen atoms with a monovalent or divalent radical.Suitable substitution groups include, for example, H, ²H, halo, C₂₋₃alkynyl, C₂₋₃ alkenyl, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃haloalkoxy, C₃₋₇ cycloalkyl, CONH₂, CONHC₁₋₃ alkyl, CONHC₆₋₁₀ aryl,SO₂NH₂, SO₂NHC₁₋₃ alkyl, SO₂NHC₆₋₁₀ aryl and 4-7 membered heterocyclylhaving 1 to 3 heteroatoms selected from N, O and S, said heterocyclyloptionally substituted one or two substituents each independentlyselected from the group consisting of: H, ²H, halo, CN, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ haloalkoxy; and the like.

The substitution group can itself be substituted. The group substitutedonto the substitution group can be carboxyl, halo; nitro, amino, cyano,hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, aminocarbonyl, —SR, thioamido, —SO₃H,—SO₂R or C₃₋₈ cycloalkyl, where R is typically hydrogen, hydroxyl orC₁₋₃ alkyl.

When the substituted substituent includes a straight chain group, thesubstitution can occur either within the chain (e.g., 2-hydroxypropyl,2-aminobutyl, and the like) or at the chain terminus (e.g.,2-hydroxyethyl, 3-cyanopropyl, and the like). Substituted substituentscan be straight chain, branched or cyclic arrangements of covalentlybonded carbon or heteroatoms.

The term “²H” refers to a heavy isotope of hydrogen that is alsoreferred to as deuterium (D). It is understood that the abovedefinitions are not intended to include impermissible substitutionpatterns (e.g., methyl substituted with five fluoro groups or a halogenatom substituted with another halogen atom). Such impermissiblesubstitution patterns are well known to the skilled artisan.

The compounds of the invention, including the compounds of formulas (I),(Ia), (II) or (III) or their tautomers, as well as the pharmaceuticallyacceptable salts, esters, metabolites and prodrugs of any of them, maycomprise asymmetrically substituted carbon atoms. Such asymmetricallysubstituted carbon atoms can result in the compounds of the inventionexisting in enantiomers, diastereomers, and other stereoisomeric formsthat may be defined, in terms of absolute stereochemistry, such as in(R)- or (S)-forms. As a result, all such possible isomers, individualstereoisomers in their optically pure forms, mixtures thereof, racemicmixtures (or “racemates”), mixtures of diastereomers, as well as singlediastereomers of the compounds of the invention are included in thepresent invention. The terms “S” and “R” configuration, as used herein,are as defined by the IUPAC 1974 RECOMMENDATIONS FOR SECTION E,FUNDAMENTAL STEREOCHEMISTRY , Pure Appl. Chem. 45:13-30 (1976). Theterms α and β are employed for ring positions of cyclic compounds. Theα-side of the reference plane is that side on which the preferredsubstituent lies at the lower numbered position. Those substituentslying on the opposite side of the reference plane are assigned βdescriptor. It should be noted that this usage differs from that forcyclic stereoparents, in which “α” means “below the plane” and denotesabsolute configuration. The terms α and β configuration, as used herein,are as defined by the CHEMICAL ABSTRACTS INDEX GUIDE-APPENDIX IV (1987)paragraph 203.

In accordance with one aspect of the present invention, new compounds,their tautomers, stereoisomers, or pharmaceutically acceptable saltsthereof or esters having a solubility enhancing moieties or prodrugsthereof are provided of the formula (I):

-   -   wherein:    -   R¹ is optionally substituted 6-10 membered aryl or 5-10 membered        heteroaryl having 1 to 4 heteroatoms each independently selected        from the group consisting of: O, N and S, said heteroaryl or        aryl each being optionally substituted with 1 to 3 substituents        each independently selected from the group consisting of: H, ²H,        halo, C₂₋₃ alkynyl, C₂₋₃ alkenyl, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy,        C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl, CONH₂,        CONHC₁₋₃ alkyl, CONHC₆₋₁₀ aryl, SO₂NH₂, SO₂NHC₁₋₃ alkyl,        SO₂NHC₆₋₁₀ aryl and 4-7 membered heterocyclyl having 1 to 3        heteroatoms selected from N, O and S, said heterocyclyl        optionally substituted one or two substituents each        independently selected from the group consisting of: H, ²H,        halo, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃        haloalkoxy;    -   R², R³ and R⁴ are each independently H, ²H, halo, hydroxy (—OH),        C₁₋₃ alkoxy, C₁₋₃ haloalkyl or C₁₋₃ alkyl, optionally        substituted with one to two of hydroxyl, halo and C₁₋₃        haloalkoxy;    -   R⁵ is —H, ²H, CH₃, CH₂F, CHF₂, CF₃, CH₂OH, C₁₋₃ alkyl,        CH₂—O—C₁₋₃ alkyl or CH₂—O—C₁₋₃ haloalkyl, said C₁₋₃ alkyl        optionally substituted with H, F, OH, C₁₋₃ alkoxy and C₁₋₃        haloalkoxy;    -   R^(5a) and R^(5b) are each independently H, ²H, C₁₋₃ alkyl, said        C₁₋₃ alkyl optionally substituted with H, F, OH, C₁₋₃ alkoxy and        C₁₋₃ haloalkoxy, or R^(5a) and R^(5b) are joined together        forming a methylene or ethylene bridging group; and    -   R^(5c) and R^(5d) are each independently H, ²H, F, —OH, C₁₋₃        alkyl, said alkyl optionally substituted with F, OH, and alkoxy        or C₁₋₃ alkoxy or R^(5c) and R^(5d) are joined together forming        a methylene, ethylene or —CH₂—O— bridging group.

In one embodiment, new compounds, their tautomers, stereoisomers orpharmaceutically acceptable salts thereof or esters having a solubilityenhancing moieties or prodrugs thereof are provided of the formula (I),

-   -   wherein:    -   R¹ is pyridinyl, pyrimidinyl, thiazolyl, indolyl, azaindolyl,        imidazolyl, pyrazinyl, quinolinyl, azaquinolinyl, isoquinolinyl        purinyl, benzothiazolyl, benzopyridyl, benzimidazolyl, phenyl or        naphthyl, each unsubstituted or substituted with 1 to 3        substituents each independently selected from the group        consisting of: H, ²H, halo, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃        haloalkyl, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl, morpholino,        piperidinyl and piperazinyl;    -   R², R³ and R⁴ are each H;    -   R⁵ is H, ²H, CH₃, CH₂F, CHF₂, CF₃, CH₂OH, C₁₋₃ alkyl, CH₂—O—C₁₋₃        alkyl, CH₂—O—C₁₋₃ alkyl or CH₂—O—C₁₋₃ haloalkyl;    -   R^(5a) and R^(5b) are each H, F, C₁₋₃ alkyl, C₁₋₃ alkoxy or        R^(5a) and R^(5b) are joined together forming a methylene or        ethylene bridging group; and    -   R^(5c) and R^(5d) are each independently H, F, C₁₋₃ alkyl, or        C₁₋₃ alkoxy or R^(5c) and R^(5d) are joined together forming a        methylene, ethylene or —CH₂—O— bridging group.    -   In a separate embodiment, R^(5a) and R^(5d) are joined together        forming a methylene, ethylene or —CH₂—O— bridging group,        provided that the O atom of the —CH₂—O— bridging group is formed        at R^(5d). In a separate embodiment, if a bridging group is        formed only one of R^(5a) and R^(5b), R^(5c) and R^(5d) or        R^(5a) and R^(5d) forms a bridging group.

In another embodiment, new compounds, their tautomers, stereoisomers orpharmaceutically acceptable salts thereof or esters having a solubilityenhancing moieties or prodrugs thereof are provided of the formula (I),

-   -   wherein:    -   R¹ is independently pyridinyl, pyrimidinyl, thiazolyl, indolyl,        imidazolyl, pyrazinyl, quinolinyl, isoquinolinyl or phenyl, each        unsubstituted or substituted with 1 to 3 substituents each        independently selected from the group consisting of: H, ²H,        halo, CN, acetylene, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,        C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl, morpholino, piperidinyl and        piperazinyl;    -   R², R³ and R⁴ are each H;    -   R⁵ is independently H, ²H, CH₃, CH₂F, CHF₂, CF₃, C₁₋₃ alkyl,        CH₂OH, CH₂—O—C₁₋₃ alkyl CH₂—O—C₁₋₃ haloalkyl;    -   R^(5a) and R^(5b) are each H; and    -   R^(5c) and R^(5d) are each H.

In another embodiment, new compounds, their tautomers, stereoisomers orpharmaceutically acceptable salts thereof or esters having a solubilityenhancing moieties or prodrugs thereof are provided of the formula (I),

-   -   wherein:    -   R¹ is pyridinyl or pyrimidinyl, substituted with 1 to 3        substituents each independently selected from the group        consisting of: H, ²H, halo, CN, acetylene, C₁₋₃ alkyl, C₁₋₃        alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl,        morpholino, piperidinyl and piperazinyl;    -   R², R³ and R⁴ are each H;    -   R⁵ is independently H, CH₃, CH₂F, CHF₂, CF₃, CH₂OH, CH₂—O—C₁₋₃        alkyl or CH₂—O—C₁₋₃ haloalkyl;    -   R^(5a) and R^(5b) are each H; and    -   R^(5c) and R^(5d) are each H.

In another embodiment, a compound or a stereoisomer, tautomer, or apharmaceutically acceptable salt thereof is selected from:3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(2-morpholinothiazol-4-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-morpholino-5-(trifluoromethyl)pyrimidin-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-fluoro-2-methylquinazolin-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-chloropyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-((1R,5S,8s)-8-amino-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoro-4-methoxypyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-cyano-3-fluoropyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyanopyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-((1S,5R,8S)-8-amino-6-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(5,6,7,8-tetrahydroquinazolin-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(dimethylamino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-((1R,5S,8s)-8-amino-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-cyano-3-fluoropyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-(2-methoxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-fluoroquinazolin-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-morpholinophenyl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3,6-bis(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(5-morpholino-2-(trifluoromethyl)phenyl)pyrazine-2-carboxamide,(±)3-amino-N-(3-((cis)-4-amino-3-fluoropiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(2-morpholinopyrimidin-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-(3,6-dihydro-2H-pyran-4-yl)-5-(trifluoromethyl)pyrimidin-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-morpholinoquinazolin-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(1-methyl-1H-indazol-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(7-fluoroisoquinolin-1-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-morpholinopyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-morpholinophenyl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(7-chloroisoquinolin-1-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-(azetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-((3S,4R)-4-amino-3-fluoropiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(2-(trifluoromethyl)-1H-indol-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(5-morpholino-2-(trifluoromethyl)phenyl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-(dimethylamino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-(4,4-difluoropiperidin-1-yl)-5-fluoropyrimidin-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(5-fluoro-2-morpholinopyrimidin-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(1-methyl-1H-indol-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(1H-indazol-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-cyano-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-fluoro-2-morpholinoquinazolin-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(2-methyl-1H-indol-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-ethoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,4-(5-amino-6-((3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)carbamoyl)pyrazin-2-yl)-5-fluoropyrimidine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-cyano-5-(trifluoromethyl)pyrimidin-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-amino-5-chloropyrimidin-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(1H-indol-4-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-morpholino-5-(trifluoromethyl)phenyl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-chloro-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(5-morpholino-2-(trifluoromethyl)phenyl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridine-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)-6-methylpyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)-6-methylpyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-3-methoxypiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoro-4-methylpyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-ethoxy-3-fluoropyridin-2-yl)pyrazine-2-carboxamide,3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(hydroxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamideand3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(methoxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide.

In another embodiment, a compound or a stereoisomer, tautomer, orpharmaceutically acceptable salt thereof, is selected from:

In a separate embodiment, compounds, their tautomers, stereoisomers, orpharmaceutically acceptable salts thereof or esters having a solubilityenhancing moieties or prodrugs thereof are provided of the formula (Ia):

-   -   wherein:    -   R¹ is optionally substituted C₆₋₁₀ aryl, said aryl being        optionally substituted with 1 to 3 substituents each        independently selected from the group consisting of: H, ²H,        halo, C₂₋₃ alkynyl, C₂₋₃ alkenyl, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy,        C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl, CONH₂,        CONHC₁₋₃ alkyl, CONHC₆₋₁₀ aryl, SO₂NH₂, SO₂NHC₁₋₃ alkyl,        SO₂NHC₆₋₁₀ aryl and 4-7 membered heterocyclyl having 1 to 3        heteroatoms selected from N, O and S, said heterocyclyl        optionally substituted one or two substituents each        independently selected from the group consisting of: H, ²H,        halo, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃        haloalkoxy;    -   R², R³ and R⁴ are each independently H, ²H, halo, hydroxy (—OH),        C₁₋₃ alkoxy, C₁₋₃ haloalkyl or C₁₋₃ alkyl, optionally        substituted with one to two of hydroxyl, halo and C₁₋₃        haloalkoxy;    -   R⁵ is independently H, ²H, CH₃, CH₂F, CHF₂, CF₃, CH₂OH, C₁₋₃        alkyl, CH₂—O—C₁₋₃ alkyl or CH₂—O—C₁₋₃ haloalkyl, said C₁₋₃ alkyl        optionally substituted with H, F, OH, C₁₋₃ alkoxy and C₁₋₃        haloalkoxy;    -   R^(5a) and R^(5b) are each independently H, ²H, C₁₋₃ alkyl, said        C₁₋₃ alkyl optionally substituted with H, F, OH, C₁₋₃ alkoxy and        C₁₋₃ haloalkoxy, or R^(5a) and R^(5b) are joined together        forming a methylene or ethylene bridging group; and    -   R^(5c) and R^(5d) are each independently H, ²H, F, —OH, C₁₋₃        alkyl, said alkyl optionally substituted with F, OH, and alkoxy        or C₁₋₃ alkoxy or R^(5c) and R^(5d) are joined together forming        a methylene, ethylene or —CH₂—O— bridging group.

In a separate embodiment, R^(5a) and R^(5d) are each independently H,²H, F, —OH, C₁₋₃ alkyl, said alkyl optionally substituted with F, OH,C₁₋₃ alkoxy or are joined together forming a methylene, ethylene or—CH₂—O— bridging group, provided that the oxygen atom of the bridginggroup is attached at R^(5d).

In a separate embodiment, if a bridging group is formed only one ofR^(5a) and R^(5b), R^(5c) and R^(5d) or R^(5a) and R^(5d) forms abridging group.

In a separate embodiment, compounds, their tautomers, stereoisomers orpharmaceutically acceptable salts thereof or esters having a solubilityenhancing moieties or prodrugs thereof are provided of the formula (Ia),

wherein:

-   -   R¹ is phenyl, substituted with one to three substituents each        independently selected from the group consisting of: halo, CF₃,        CN, NH₂, NHCOC₁₋₃alkyl, acetylene, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃        haloalkyl, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl, morpholino,        piperinyl, piperazinyl, N-methylpiperazinyl, SO₂C₁₋₃ alkyl and        COOCH₃;    -   R², R³ and R⁴ are each H;    -   R⁵ is independently H, CH₃, CH₂F, CHF₂, CF₃, CH₂OH, CH₂—O—C₁₋₃        alkyl;    -   R^(5a) and R^(5b) are each H or R^(5a) and R^(5b) are joined        together forming a methylene, ethylene or —CH₂—O— bridging        group; and    -   R^(5c) and R^(5d) are each independently H, F C₁₋₃ alkyl, or        C₁₋₃ alkoxy or R^(5c) and R^(5d) are joined together forming a        methylene, ethylene or —CH₂—O— bridging group.

In a separate embodiment, R^(5a) and R^(5d) are each independently H,²H, F, —OH, C₁₋₃ alkyl, said alkyl optionally substituted with F, OH,and alkoxy or C₁₋₃ alkoxy or R^(5c) and R^(5d) are joined togetherforming a methylene, ethylene or —CH₂—O— bridging group.

In a separate embodiment, if a bridging group is formed only one ofR^(5a) and R^(5b), R^(5c) and R^(5d) or R^(5a) and R^(5d) forms abridging group.

In another embodiment, new compounds, their tautomers, stereoisomers orpharmaceutically acceptable salts thereof or esters having a solubilityenhancing moieties or prodrugs thereof are provided of the formula (Ia),

-   -   wherein:    -   R¹ is phenyl, substituted with one or two substituents each        independently selected from the group consisting of: H, ²H,        halo, CN, acetylene, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,        C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl, morpholino, piperidinyl,        piperazinyl and COOCH₃;    -   R², R³ and R⁴ are each H;    -   R⁵ is independently H, CH₃, CH₂F, CHF₂, CF₃, CH₂OH, CH₂—O—C₁₋₃        alkyl;    -   R^(5a) and R^(5b) are each H or R^(5a) and R^(5b) are joined        together forming a methylene or ethylene bridging group; and    -   R^(5c) and R^(5d) are each independently H, F C₁₋₃ alkyl, C₁₋₃        alkoxy or R^(5c) and R^(5d) are joined together forming a        methylene, ethylene or —CH₂—O— bridging group.

In another embodiment, a compound or a stereoisomer, tautomer, orpharmaceutically acceptable salt thereof, is selected from:3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-morpholino-5-(trifluoromethyl)phenyl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(5-morpholino-2-(trifluoromethyl)phenyl)pyrazine-2-carboxamide,3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-morpholinophenyl)pyrazine-2-carboxamide,and 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridine-2-yl)-6-(3-morpholinophenyl)pyrazine-2-carboxamide.

In another embodiment, a compound or a stereoisomer, tautomer, or apharmaceutically acceptable salt thereof, is selected from:

In a separate embodiment, compounds, their tautomers, stereoisomers orpharmaceutically acceptable salts thereof or esters having a solubilityenhancing moieties or prodrugs thereof are provided of the formula (II):

wherein:

-   X is N or CR;    -   R, R², R³ and R⁴ are each independently H, ²H, halo, hydroxy        (—OH), C₁₋₃ alkoxy, C₁₋₃ haloalkyl CONH₂, CONHC₁₋₃ alkyl,        CONHC₆₋₁₀ aryl, SO₂NH₂, SO₂NHC₁₋₃ alkyl, SO₂NHC₆₋₁₀ aryl or C₁₋₃        alkyl, optionally substituted with one to two of hydroxyl, halo        and C₁₋₃ haloalkoxy;    -   R⁵ is —H, ²H, CH₃, CH₂F, CHF₂, CF₃, CH₂OH, C₁₋₃ alkyl,        CH₂—O—C₁₋₃ alkyl or CH₂—O—C₁₋₃ haloalkyl, said C₁₋₃ alkyl        optionally substituted with H, F, OH, C₁₋₃ alkoxy and C₁₋₃        haloalkoxy;    -   R^(5a) and R^(5b) are each independently H, ²H, C₁₋₃ alkyl, said        C₁₋₃ alkyl optionally substituted with H, F, OH, C₁₋₃ alkoxy and        C₁₋₃ haloalkoxy, or R^(5a) and R^(5b) are joined together        forming a methylene or ethylene bridging group;    -   R^(5c) and R^(5d) are each independently H, ²H, F, —OH, C₁₋₃        alkyl, said alkyl optionally substituted with F, OH, and alkoxy        or C₁₋₃ alkoxy or R^(5c) and R^(5d) are joined together forming        a methylene, ethylene or —CH₂—O— bridging group; or    -   R^(5a) and R^(5d) are optionally joined together forming a        methylene, ethylene or —CH₂—O— bridging group, provided that the        O atom of the —CH₂—O— bridging group is bonded at R^(5d); and    -   R⁶, R⁸ and R⁸ are each independently selected from H, ²H, halo,        C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl        and 4-7 membered heterocyclyl, optionally substituted with 1 to        3 substituents selected from H, halo, hydroxyl, C₂₋₃ alkynyl,        C₂₋₃ alkenyl, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃        haloalkoxy and C₃₋₇ cycloalkyl; or    -   wherein R⁶ and R⁸ optionally forms a partially saturated        carbobicyclic ring or heterobicyclic ring with the heteroaryl        ring, said carbobicyclic ring or heterobicyclic ring optionally        substituted with 1 to 3 groups selected from: H, ²H, halo, C₁₋₃        haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl and 4-7        membered heterocyclyl.

In a separate embodiment, compounds, their tautomers, stereoisomers orpharmaceutically acceptable salts thereof or esters having a solubilityenhancing moieties or prodrugs thereof are provided of the formula (II),

wherein:

-   X is CR;    -   R², R³ and R⁴ are each H;    -   R⁵ is independently H, CH₃, CH₂F, CHF₂, CF₃, CH₂OH, CH₂—O—C₁₋₃        alkyl    -   R^(5a) and R^(5b) are each H or R^(5a) and R^(5b) are joined        together forming a methylene or ethylene bridging group;    -   R^(5c) and R^(5d) are each independently H, F, C₁₋₃ alkyl, or        C₁₋₃ alkoxy or R^(5c) and R^(5d) are joined together forming a        methylene, ethylene or —CH₂—O— bridging group; and    -   R⁶ and R⁷ are each independently selected from H, halo, C₁₋₃        haloalkyl, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl, morpholino,        piperinyl and piperazinyl.    -   In another embodiment, a compound or a pharmaceutically        acceptable salt thereof is selected from:-   3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-chloropyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoro-4-methoxypyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyanopyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-cyano-3-fluoropyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-(2-methoxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   (±)3-amino-N-(3-((cis)-4-amino-3-fluoropiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-((3    S,4R)-4-amino-3-fluoropiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-cyano-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-ethoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-chloro-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-aminopiperidin-1-yl)-6-methylpyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-aminopiperidin-1-yl)-6-methylpyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-3-methoxypiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoro-4-methylpyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-ethoxy-3-fluoropyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(hydroxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;    and-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(methoxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide.    In another embodiment, a compound or a pharmaceutically acceptable    salt thereof is selected from:-   3-amino-N-(3-(4-amino-4-(ethoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-(ethoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-((difluoromethoxy)methyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-isopropoxypyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-cyclopropoxypyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-cyanopyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-phenoxypyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(5-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-3-fluoro-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-(cyanomethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-(cyanomethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-3-fluoro-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-((3 S,    4R)-4-amino-3-fluoro-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-ethoxypyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-3-fluoro-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;    and-   3-amino-N-(3-(4-amino-4-(cyanomethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide.    -   In another embodiment, a compound or a pharmaceutically        acceptable salt thereof is selected from:-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3    morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-fluoro-2-methylquinazolin-4-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(5,6,7,8-tetrahydroquinazolin-4-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-fluoroquinazolin-4-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-morpholinoquinazolin-4-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(7-fluoroisoquinolin-1-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(7-chloroisoquinolin-1-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-fluoro-2-morpholinoquinazolin    -4-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide;    and-   3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide.    In another embodiment a compound or a pharmaceutically acceptable    salt thereof is selected from:-   3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(1-morpholinoisoquinolin-3-yl)pyrazine-2-carboxamide.    -   In another embodiment a compound or a pharmaceutically        acceptable salt thereof is selected from:-   3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;    and-   3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide.

In a separate embodiment, compounds, their tautomers, stereoisomers orpharmaceutically acceptable salts thereof or esters having a solubilityenhancing moieties or prodrugs thereof are provided of the formula(III):

-   -   wherein:    -   R¹ is optionally substituted 6-10 membered aryl or 5-10 membered        heteroaryl having 0 to 4 heteroatoms each independently selected        from the group consisting of: O, N and S, said heteroaryl or        aryl each being optionally substituted with 1 to 3 substituents        each independently selected from the group consisting of: H, ²H,        halo, C₂₋₃ alkynyl, C₂₋₃ alkenyl, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy,        C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl, CONH₂,        CONHC₁₋₃ alkyl, CONHC₆₋₁₀ aryl, SO₂NH₂, SO₂NHC₁₋₃ alkyl,        SO₂NHC₆₋₁₀ aryl and 4-7 membered heterocyclyl having 1 to 3        heteroatoms selected from N, O and S, said heterocyclyl        optionally substituted one or two substituents each        independently selected from the group consisting of: H, ²H,        halo, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃        haloalkoxy;    -   R², R³ and R⁴ are each independently H, ²H, halo, hydroxy (—OH),        C₁₋₃ alkoxy, C₁₋₃ haloalkyl or C₁₋₃ alkyl, optional substituted        with one to two of hydroxyl, halo and C₁₋₃ haloalkoxy; and    -   R⁹ is H or 4-7 membered heterocyclyl or heterobicyclyl having 1        or 2 heteroatoms selected from N, O and S, SO, SO₂, said        heterocycyl or heterobicylyl substituted with 1 to 4        substituents each independently selected from the group        consisting of: H, ²H, amino (NH₂), halo, CN, acetylene, C₁₋₃        alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₃₋₇        cycloalkyl, C₂₋₃ alkynyl, C₂₋₃ alkenyl, COOC₁₋₃ alkyl, CONH₂,        CONHC₁₋₃ alkyl, CONHC₆₋₁₀ aryl, SO₂NH₂, SO₂NHC₁₋₃ alkyl,        SO₂NHC₆₋₁₀ aryl, SO(N)NHC₁₋₃ alkyl, SO(N)NHC₆₋₁₀ aryl,        —O—(CH₂)-heterocyclyl (n=1-3), CO NH₂, said C₁₋₃ alkyl or        —O—(CH₂)-heterocyclyl, said heterocylyl having 1 to 3        heteroatoms selected from N, O and S, SO, SO₂ each optionally        substituted with 1 to 4 substituents selected from NH₂, OH,        halo, C₁₋₃ alkoxy and C₁₋₃ haloalkoxy.    -   In one embodiment, R⁹ is a substituted piperdinyl. In one        embodiment, R⁹ is a substituted piperdinyl selected from the        structures:

-   -   In a separate embodiment, R⁹ is selected from piperidinyl,        piperazinyl, 1,2-oxazinane, 2-oxopiperazinyl, 2-oxopiperidinyl        and morpholinyl, optionally substituted.

As used herein, the term “pharmaceutically acceptable salts” refers tothe nontoxic acid or alkaline earth metal salts of the compounds ofFormulas (I), (Ia), (II) or (III). These salts can be prepared in situduring the final isolation and purification of the compounds of Formulas(I), (Ia), (II) or (III), or by separately reacting the base or acidfunctions with a suitable organic or inorganic acid or base,respectively. Representative salts include but are not limited to thefollowing: acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate,glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate,persulfate, 3-phenylproionate, picrate, pivalate, propionate, succinate,sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate.Also, the basic nitrogen-containing groups can be quaternized with suchagents as loweralkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides, and iodides; dialkyl sulfates like dimethyl,diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides like benzyl and phenethyl bromides, and others. Water oroil-soluble or dispersible products are thereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, methanesulfonic acid, succinic acidand citric acid. Basic addition salts can be prepared in situ during thefinal isolation and purification of the compounds of formula (I), orseparately by reacting carboxylic acid moieties with a suitable basesuch as the hydroxide, carbonate or bicarbonate of a pharmaceuticallyacceptable metal cation or with ammonia, or an organic primary,secondary or tertiary amine. Pharmaceutically acceptable salts include,but are not limited to, cations based on the alkali and alkaline earthmetals, such as sodium, lithium, potassium, calcium, magnesium, aluminumsalts and the like, as well as nontoxic ammonium, quaternary ammonium,and amine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like.

As used herein, the term “pharmaceutically acceptable ester” refers toesters, which hydrolyze in vivo and include those that break downreadily in the human body to leave the parent compound or a saltthereof. Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include formates, acetates, propionates,butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention. The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound of the above formula,for example by hydrolysis in blood. A thorough discussion is provided inT. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

It will be apparent to those skilled in the art that the compounds ofthe invention, including the compounds of formulas (I), (Ia), (II) or(III) or their tautomers, prodrugs and stereoisomers, as well as thepharmaceutically acceptable salts, esters and prodrugs of any of them,may be processed in vivo through metabolism in a human or animal body orcell to produce metabolites. The term “metabolite” as used herein refersto the formula of any derivative produced in a subject afteradministration of a parent compound. The derivatives may be producedfrom the parent compound by various biochemical transformations in thesubject such as, for example, oxidation, reduction, hydrolysis, orconjugation and include, for example, oxides and demethylatedderivatives. The metabolites of a compound of the invention may beidentified using routine techniques known in the art. See, e.g.,Bertolini, G. et al., J. Med. Chem. 40:2011-2016 (1997); Shan, D. etal., J. Pharm. Sci. 86(7):765-767; Bagshawe K., Drug Dev. Res.34:220-230 (1995); Bodor, N., Advances in Drug Res. 13:224-331 (1984);Bundgaard, H., Design of Prodrugs (Elsevier Press 1985); and Larsen, I.K., Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991). Itshould be understood that individual chemical compounds that aremetabolites of the compounds of formulas (I), (II) or (III) or theirtautomers, prodrugs and stereoisomers, as well as the pharmaceuticallyacceptable salts, esters and prodrugs of any of them, are includedwithin the invention.

In other aspects, the present invention provides a method for treatingprotein kinase C related disorders in a human or animal subject inrecognized need of such treatment comprising administering to saidsubject an amount of a compound of formula (I), (Ia), (II) or (III)effective to PKC activity in the subject. PKC inhibitors useful in thepractice of the present invention may inhibit several isoforms of thePKC, in particular they may selectively inhibit specific PKC isoforms(e.g., selective PKC inhibitors or isozyme-selective PKC inhibitors).The PKC inhibitors are able to selectively inhibit PKC isoforms whichare selected from the classical PKC isoforms (α, β1, β2, γ) and novelPKC isoforms (δ, ε, η, θ) or atypical isoforms (ζ, ι), more preferablyselected from the α, β (β1 and β2 isoforms) and θ PKC isoforms.Preferred PKC inhibitors are able to selectively inhibit PKC α and θisoforms. Suitable PKC inhibitors include maleimide derivatives, such ascompounds described in U.S. Pat. Nos. 5,545,636; 5,668,152; 5,672,681;5,698,578; 5,710,145; 6,645,970; 7,220,774; 7,235,555; US PublicationNo. 2008/0318975; European Patent Nos. 0776895 B1; 0817627 B1; 1449529B1; 1337527 B1; and PCT Publication Nos. WO03/082859; and WO07/006,533Each of the references cited above are incorporated herein by reference.As used herein, the term “PKC inhibitor” refers to a protein kinase Cinhibitor that may be pan (multi-subtype) or selective to one or morePKC isozymes. The term PKC generally refers to the entire family ofisoforms: conventional isoforms; alpha, beta, and gamma, novel isoforms;delta, epsilon, eta, and theta, and atypical isoforms; zeta, and iotaThe term “selective PKC inhibitor” refers to a PKC inhibitor thatpossesses a selectivity of at least about 20 fold for one or more PKCisoforms as compared to the other PKC isoforms. Preferably, theselectivity is at least about 100 fold, more preferably at least about500 fold, most preferably at least about 1,000 or at least about 2,000fold The term “selective PKC alpha/theta inhibitor”, “selective PKC α/θinhibitor” refers to a protein kinase C inhibitor that is more selectivefor the alpha and/or theta PKC isoform of PKC than the other disclosedisoforms of PKC. For example, PKC alpha or PKC alpha and theta, over theother named PKC isoforms of at least about 20 fold (preferably at leastabout 100, more preferably at least about 500, most preferably at leastabout 1,000 or at least about 2,000 fold).

Differential regulation of GSK3β by protein kinase C isotopes wasdescribed by Goode, et al in the publication, J. Biol. Chem., Vol. 267,pp 16878-16882 (1992). More recently, dual regulation of GSK3α/β byprotein kinase C isotope alpha and Akt was described to promote thrombinmediated Integrin α_(11b)/β₃ activation and granule secretion inplatelets by Moore, et al in the publication J. Biol. Chem., Vol. 288,pp 3918-3928 (2013).

In other aspects, the present invention provides a method for treatingprotein kinase related disorders, specifically protein kinase C, alpha,theta (PKCα/θ) related disorders related disorders in a human or animalsubject in recognized need of such treatment comprising administering tosaid subject an amount of a compound of formula (I), (Ia), (II) or (III)effective to treat cancer or tumor growth associated with the PKCα/θ inthe subject.

In other aspects, the present invention provides a method for treatingimmune related disorders, including but not limited to autoimmunediseases, allergic reaction and tissue transplant rejection, in a humanor animal subject in recognized need of such treatment comprisingadministering to said subject an amount of a compound of formula (I),(II) or (III) effective to reduce or prevent tumor growth in thesubject. In other aspects, the present invention provides a method fortreating malignant solid tumors in a human or animal subject inrecognized need of such treatment comprising administering to saidsubject an amount of a compound of formula (I), (II) or (III) effectiveto reduce or prevent tumor growth in the subject. In addition to apotential role in cancer treatment and myeloproliferative diseases, suchinhibitor could be useful to control expansion of immune cells in otherpathologic condition such as autoimmune diseases, allergic reactions andin organ transplantation rejection syndromes. Support that the inventedselective PKC inhibitor of the present invention would be effective attreating immune related disorders is provided by the recent disclosurethat sotrastaurin represents a new class of immunosuppressive agentsaffecting early T-Cell Activation (Evenou, et al, “The Journal ofPharmacology and Experimental Therapeutics,” Vol. 330 pp. 792-801,2009).

In other aspects, the present invention provides a method for treatingcancer, tumors in a human or animal subject in recognized need of suchtreatment comprising administering to said subject an amount of acompound of formula (I), (Ia), (II) or (III) effective to reduce orprevent tumor growth in the subject. In other aspects, the presentinvention provides a method for treating malignant solid tumors in ahuman or animal subject in recognized need of such treatment comprisingadministering to said subject an amount of a compound of formula (I),(Ia), (II) or (III) effective to reduce or prevent tumor growth in thesubject.

In other aspects, the present invention provides a method for treatinguveal melanoma, including uveal melanoma harboring GNAQ or GNA11mutations in a human or animal subject in recognized need of suchtreatment comprising administering to said subject an amount of acompound of formula (I), (Ia, (II) or (III) effective to reduce orprevent tumor growth in the subject.

In other aspects, the present invention provides a method for treatinglymphoma, including diffuse large B-cell lymphoma (DLBCL), in a human oranimal subject in recognized need of such treatment comprisingadministering to said subject an amount of a compound of formula (I),(Ia), (II) or (III) effective to reduce or prevent tumor growth in thesubject.

In other aspects, the present invention provides a method for treatingibrutinib resistant cancers in a human or animal subject in recognizedneed of such treatment comprising administering to said subject anamount of a compound of formula (I), (Ia), (II) or (III) effective toreduce or prevent tumor growth in the subject. PKC is immediatelydownstream from Bruton's Tyrosine Kinase with regards to B-celllymphomas and hematological cancers and provide support that theinvented PKC inhbitiors would be effective at treating ibrutinibresistant cancers and diseases. Woyach, et al have described andidentified certain specific mutations that may mediate ibrutinibresistance in the publication, J. New England Medicine, DOI:10.1056/NEJMoa1400029, 2014.

In other aspects, the present invention provides a method for treatingprotein kinase related disorders, specifically protein kinase C,(PKCα/θ) related disorders in a human or animal subject in recognizedneed of such treatment comprising administering to said subject anamount of a compound of formula (I), (Ia), (II) or (III) effective toreduce or prevent tumor growth associated with the PKCα/θ relateddisorder in the subject. The term “a therapeutically effective amount”of a PKC inhibitor refers to an amount of the PKC inhibitor that willelicit a biological or medical response in a subject, for example,reduction or inhibition of an enzyme or the activity of a protein,and/or ameliorate symptoms, alleviate conditions, slow or delay diseaseprogression, or prevent a disease, etc. In one non-limiting embodiment,the term “a therapeutically effective amount” refers to the amount ofPKC inhibitor, that when administered to a subject, is effective to (1)at least partially alleviate, inhibit, prevent and/or ameliorate acondition, or a disorder or a disease mediated by or associated with theactivity of PKC, such as for example B-cell lymphoma having chronicactive B-cell receptor signalling (e.g., CD79 mutant diffuse-largeB-cell lymphoma) or uveal melanoma harboring GNAQ or GNA11 mutations;and/or is effective to (2) at least partially reduce the size (tumorvolume) or inhibit the further growth of tumors (solid or liquid). Inanother non-limiting embodiment, the term “a therapeutically effectiveamount” refers to the amount of the compound of the present inventionthat, when administered to a subject, cell, or a tissue, or anon-cellular biological material, or a medium, is effective to at leastpartially reduce or inhibit the growth of B-cell lymphoma having chronicactive B-cell-receptor signaling (preferably, a CD79 mutantdiffuse-large B-cell lymphoma) or uveal melanoma harboring (GNAQ orGNA11 mutations.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman. As used herein, the term “inhibit”, “inhibition” or “inhibiting”refers to the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process. As used herein, the term “treat”,“treating” or “treatment” of any disease or disorder, refers (i) toameliorating the disease or disorder (i.e., slowing or arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof (ii) to alleviating or ameliorating at least onephysical parameter including those which may not be discernible by thepatient; (iii) to modulating the disease or disorder, either physically,(e.g., stabilization of a discernible symptom), physiologically, {e.g.,stabilization of a physical parameter), or both; or (iv) to preventingor delaying the onset or development or progression of the disease ordisorder in general, the term “treating” or “treatment” describes themanagement and care of a patient for the purpose of combating thedisease, condition, or disorder and includes the administration of a PKCinhibitor to prevent the onset of the symptoms or complications,alleviating the symptoms or complications, or eliminating the disease,condition or disorder.

In yet other aspects, the present invention provides methods fortreating PKC related disorders, including cancers disclosed herein, in ahuman or animal subject in need of such treatment comprisingadministering to said subject an amount of a compound of formula (I),(Ia), (II) or (III) effective to reduce or prevent tumor growth in thesubject in combination with at least one additional agent for thetreatment of cancer. A number of suitable anticancer agents to be usedas combination therapeutics are contemplated for use in the methods ofthe present invention. Indeed, the present invention contemplates, butis not limited to, administration of numerous anticancer agents such as:agents that induce apoptosis; polynucleotides (e.g., ribozymes);polypeptides (e.g., enzymes); drugs; biological mimetics; alkaloids;alkylating agents; antitumor antibiotics; antimetabolites; hormones;platinum compounds; monoclonal antibodies conjugated with anticancerdrugs, toxins, and/or radionuclides; biological response modifiers (e.g.interferons [e.g. IFN-a, etc.] and interleukins [e.g. IL-2, etc.],etc.); adoptive immunotherapy agents; hematopoietic growth factors;agents that induce tumor cell differentiation (e.g. all-trans-retinoicacid, etc.); gene therapy reagents; antisense therapy reagents andnucleotides; tumor vaccines; inhibitors of angiogenesis, and the like.Numerous other examples of chemotherapeutic compounds and anticancertherapies suitable for coadministration with the disclosed compounds offormula (I), (II) or (III) are known to those skilled in the art.

In preferred embodiments, anticancer agents to be used in combinationwith compounds of the present invention comprise agents that induce orstimulate apoptosis. Agents that induce apoptosis include, but are notlimited to, radiation (e.g., W); kinase inhibitors (e.g., EpidermalGrowth Factor Receptor [EGFR] kinase inhibitor, Vascular Growth FactorReceptor [VGFR] kinase inhibitor, Fibroblast Growth Factor Receptor[FGFR] kinase inhibitor, Platelet-derived Growth Factor Receptor [PGFR]I kinase inhibitor, and Bcr-Ab1 kinase inhibitors such as STI-571,Gleevec, and Glivec]); antisense molecules; antibodies [e.g., Herceptinand Rituxan]; anti-estrogens [e.g., raloxifene and tamoxifen];anti-androgens [e.g., flutamide, bicalutamide, finasteride,aminoglutethamide, ketoconazole, and corticosteroids]; cyclooxygenase 2(COX-2) inhibitors [e.g., Celecoxib, meloxicam, NS-398, andnon-steroidal antiinflammatory drugs (NSAIDs)]; and cancerchemotherapeutic drugs [e.g., irinotecan (Camptosar), CPT-11,fludarabine (Fludara), dacarbazine (DTIC), dexamethasone, mitoxantrone,Mylotarg, VP-16, cisplatinum, 5-FU, Doxrubicin, Taxotere or taxol];cellular signaling molecules; ceramides and cytokines; and staurosprine,and the like.

In yet other aspects, the present invention provides therapeuticcompositions comprising at least one compound of formula (I), (Ia), (II)or (III) in combination with a pharmaceutically acceptable carrier, andoptionally with one or more additional agents for the treatment ofcancer, as are commonly employed in cancer therapy.

The term “cancer” refers to cancer diseases that can be beneficiallytreated by the inhibition of PKC, including, for example, solid cancers,such as carcinomas (e.g., of the lungs, pancreas, thyroid, ovarian,bladder, breast, prostate, or colon), melanomas, myeloid disorders(e.g., uveal melanoma, myeloid leukemia, multiple myeloma anderythroleukemia), adenomas (e.g., villous colon adenoma) and sarcomas(e.g., osteosarcoma).

“PKC inhibitor” is used herein to refer to a compound that exhibits anIC₅₀ with respect to PKCα/θ activity of less than about 100 nM asmeasured in the assays described hereinbelow. In some embodiments a PKCinhibitor has an IC₅₀ with respect to PKCα/θ activity of less than about50 nM as measured in the assays described hereinbelow. In still otherembodiments a PKC inhibitor has an IC₅₀ with respect to PKCα/θ activityof less than about 10 nM as measured in the assays describedhereinbelow.

In another aspect, the present invention relates to methods ofinhibiting at least one PKC isoform in a subject, or treating abiological condition mediated by the PKC isoform, including the PKCisoform signaling pathway, in a subject, comprising the step ofadministering a therapeutic composition comprising at least one compoundof formula (I), (Ia), (II) or (III) effective to inhibit the PKC isoform(PKCα, PKCθ) or PKC isoform signaling pathway in the subject. Thetherapeutic compositions are useful for treating patients with a needfor such inhibitors (e.g., those suffering from cancer mediated byabnormal PKC signaling).

In another aspect, the present invention relates to methods ofinhibiting at least one serine/threonine kinase selected from PKCα orPKCθ in a subject, or treating a biological condition mediated by atleast one of PKCα or PKCθ, comprising the step of administering atherapeutic composition comprising at least one compound of formula (I),(Ia), (II) or (III) effective to inhibit the kinase in the subject. Thetherapeutic compounds are useful for treating patients with a need forsuch inhibitors (e.g., those suffering from cancer mediated by abnormalPKC receptor signaling).

In another aspect, the present invention relates to methods ofinhibiting the activity of PKCα or PKCθ in a subject, or treating abiological condition mediated by at least one of PKCα or PKCθ in a humanor animal subject in need of such treatment, comprising the step ofadministering to the subject at least one compound of formula (I), (Ia)(II) or (III) in an amount effective to inhibit the kinase in thesubject. The therapeutic compounds are useful for treating patients witha need for such inhibitors (e.g., those suffering from cancer mediatedby abnormal serine/threonine kinase receptor signaling).

In other aspects, the present invention relates to the processes forpreparing the compounds of Formulas (I), (Ia), (II) or (III), and to thesynthetic intermediates useful in such processes, as described in detailbelow.

Synthetic Methods

Compounds of the invention (Formulas (I), (Ia), (II) or (III)) can beobtained through procedures known to the skilled in the art (Methods1-6). For example, as shown in Scheme 1 (Method 1),3-Amino-6-substituted-pyrazine-2-carboxylic acid can be prepared fromits corresponding methyl 3-Amino-6-substituted-pyrazine-2-carboxylatestarting from methyl 3-amino-6-bromopyrazine-2-carboxylate. A protected(1-(2-aminopyridin-3-yl)piperidin-4-yl) compound (e.g. tert-butyl(1-(2-aminopyridin-3-yl)piperidin-4-yl)carbamate), is then preparedstarting from 3-fluoro-2-nitropyridine. The methyl3-Amino-6-substituted-pyrazine-2-carboxylate is then reacted with aprotected (1-(2-aminopyridin-3-yl)piperidin-4-yl) compound, thende-protected to yield a3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-substituted-pyrazine-2-carboxamide of Formulas (I), (Ia), (II) or (III).

Alternatively,3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-substituted-pyrazine-2-carboxamideof Formulas (I), (Ia), (II), or (III), can be prepared in one lesssynthetic step, as depicted in Method 2 (Scheme 2). For example, asshown in Scheme 2, 3-Amino-6-substituted-pyrazine-2-carboxylic acid canbe prepared from its corresponding methyl3-Amino-6-substituted-pyrazine-2-carboxylate starting from methyl3-amino-6-bromopyrazine-2-carboxylate. A protected(1-(2-aminopyridin-3-yl)piperidin-4-yl) compound (e.g. tert-butyl(1-(2-aminopyridin-3-yl)piperidin-4-yl)carbamate), is then preparedstarting from 3-fluoro-2-nitropyridine. The methyl3-Amino-6-substituted-pyrazine-2-carboxylate is then reacted with aprotected (1-(2-aminopyridin-3-yl)piperidin-4-yl) compound, thende-protected to yield a3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-substituted-pyrazine-2-carboxamide of Formulas (I), (Ia), (II) or (III).

In an alternative manner,3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-substituted-pyrazine-2-carboxamideof Formulas (I), (Ia), (II), or (III) can be obtained as depicted inMethod 3 (Scheme 3). For example, starting from3-fluoro-2-nitropyridine, a protected(1-(2-aminopyridin-3-yl)piperidin-4-yl) compound is prepared. Theprotected (1-(2-aminopyridin-3-yl)piperidin-4-yl) compound is thenreacted with 3-amino-6-bromopyrazine-2-caboxylic acid or a protectedacid (e.g. methyl 3-amino-6-bromopyrazine-2-carboxylate) to produce a3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-bromo-pyrazine-2-carboxamide. The3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-bromo-pyrazine-2-carboxamideis converted in two steps to the3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-substituted-pyrazine-2-carboxamideof Formulas (I), (Ia), (II) or (III).

In an alternative manner,3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-substituted-pyrazine-2-carboxamideof Formulas (I), (Ia), (II), or (III) can be obtained as depicted inMethod 4 (Scheme 4). For example, starting from3-fluoro-2-nitropyridine, a protected(1-(2-aminopyridin-3-yl)piperidin-4-yl) compound is prepared. Theprotected (1-(2-aminopyridin-3-yl)piperidin-4-yl) compound is thenreacted with 3-amino-6-bromopyrazine-2-caboxylic acid or a protectedacid (e.g. methyl 3-amino-6-bromopyrazine-2-carboxylate) to produce a3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-bromo-pyrazine-2-carboxamide. The3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-bromo-pyrazine-2-carboxamideis converted in fewer steps to the3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-substituted-pyrazine-2-carboxamideof Formulas (I), (Ia), (II) or (III).

In an alternative manner,3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-substituted-pyrazine-2-carboxamideof Formulas (I), (Ia), (II), or (III) can be obtained as depicted inMethod 5 (Scheme 5). For example,3-Amino-6-substituted-pyrazine-2-carboxylic acid can be prepared fromits corresponding methyl 3-Amino-6-substituted-pyrazine-2-carboxylatestarting from methyl 3-amino-6-bromopyrazine-2-carboxylate. The3-Amino-6-substituted-pyrazine-2-carboxylic acid is then reacted with2-amino-3-iodo-pyridine to produce Intermediate 12, which is thenconverted to (1-(2-aminopyridin-3-yl)piperidin-4-yl) compound, thende-protected to yield a3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-substituted-pyrazine-2-carboxamideof Formulas (I), (Ia), (II) or (III).

In yet another alternative manner,3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-substituted-pyrazine-2-carboxamideof Formulas (I), (Ia), (II), or (III), can be prepared in one lesssynthetic step as depicted in Method 6 (Scheme 6). For example, a3-Amino-6-halo-substituted-pyrazine-2-carboxylic acid can be preparedfrom its corresponding methyl3-Amino-6-substituted-pyrazine-2-carboxylate starting from methyl3-amino-6-bromopyrazine-2-carboxylate in one less step. The3-Amino-6-substituted-pyrazine-2-carboxylic acid is then reacted with2-amino-3-iodo-pyridine to produce Intermediate 12, which is thenconverted to (1-(2-aminopyridin-3-yl)piperidin-4-yl) compound, thende-protected to yield a3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-substituted-pyrazine-2-carboxamideof Formulas (I), (Ia), (II) or (III).

The compounds of the invention are useful in vitro or in vivo ininhibiting the growth of cancer cells. The compounds may be used aloneor in compositions together with a pharmaceutically acceptable carrieror excipient. Suitable pharmaceutically acceptable carriers orexcipients include, for example, processing agents and drug deliverymodifiers and enhancers, such as, for example, calcium phosphate,magnesium stearate, talc, monosaccharides, disaccharides, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, lowmelting waxes, ion exchange resins, and the like, as well ascombinations of any two or more thereof. Other suitable pharmaceuticallyacceptable excipients are described in “Remington's PharmaceuticalSciences,” Mack Pub. Co., New Jersey (1991), incorporated herein byreference.

Effective amounts of the compounds of the invention generally includeany amount sufficient to detectably inhibit the disclosed PKC isoformactivity by any of the assays described herein, by other PKC activityassays known to those having ordinary skill in the art or by detectingan inhibition or alleviation of symptoms of cancer.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. It will beunderstood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination, and the severity of the particular diseaseundergoing therapy. The therapeutically effective amount for a givensituation can be readily determined by routine experimentation and iswithin the skill and judgment of the ordinary clinician.

For purposes of the present invention, a therapeutically effective dosewill generally be a total daily dose administered to a host in single ordivided doses may be in amounts, for example, of from 0.001 to 1000mg/kg body weight daily and more preferred from 1.0 to 30 mg/kg bodyweight daily. Dosage unit compositions may contain such amounts ofsubmultiples thereof to make up the daily dose.

The compounds of the present invention may be administered orally,parenterally, sublingually, by aerosolization or inhalation spray,rectally, or topically in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles as desired. Topical administration may also involve the useof transdermal administration such as transdermal patches orionophoresis devices. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordi-glycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols, which are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, cyclodextrins, and sweetening,flavoring, and perfuming agents.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott, Ed.,Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p.33 et seq. (1976).

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more other agents used in the treatment of cancer. The compoundsof the present invention are also useful in combination with knowntherapeutic agents and anti-cancer agents, and combinations of thepresently disclosed compounds with other anti-cancer or chemotherapeuticagents are within the scope of the invention. Examples of such agentscan be found in Cancer Principles and Practice of Oncology, V. T. Devitaand S. Hellman (editors), 6^(th) edition (Feb. 15, 2001), LippincottWilliams & Wilkins Publishers. A person of ordinary skill in the artwould be able to discern which combinations of agents would be usefulbased on the particular characteristics of the drugs and the cancerinvolved. Such anti-cancer agents include, but are not limited to, thefollowing: estrogen receptor modulators, androgen receptor modulators,retinoid receptor modulators, cytotoxic/cytostatic agents,antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoAreductase inhibitors and other angiogenesis inhibitors, inhibitors ofcell proliferation and survival signaling, apoptosis inducing agents andagents that interfere with cell cycle checkpoints. The compounds of theinvention are also useful when co-administered with radiation therapy.

Therefore, in one embodiment of the invention, the compounds of theinvention are also used in combination with known anticancer agentsincluding, for example, estrogen receptor modulators, androgen receptormodulators, retinoid receptor modulators, cytotoxic agents,antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoAreductase inhibitors, HIV protease inhibitors, reverse transcriptaseinhibitors, and other angiogenesis inhibitors.

Estrogen receptor modulators are compounds that interfere with orinhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

Androgen receptor modulators are compounds which interfere with orinhibit the binding of androgens to an androgen receptor. Representativeexamples of androgen receptor modulators include finasteride and other5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole,and abiraterone acetate. Retinoid receptor modulators are compoundswhich interfere or inhibit the binding of retinoids to a retinoidreceptor. Examples of retinoid receptor modulators include bexarotene,tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, LX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N4-carboxyphenyl retinamide.

Cytotoxic and/or cytostatic agents are compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell mytosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, inhibitors of kinases involvedin mitotic progression, antimetabolites; biological response modifiers;hormonal/anti-hormonal therapeutic agents, haematopoietic growthfactors, monoclonal antibody targeted therapeutic agents, topoisomeraseinhibitors, proteasome inhibitors and ubiquitin ligase inhibitors.Examples of cytotoxic agents include, but are not limited to, sertenef,cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine,prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin,oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfantosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa,lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum,benzylguanine, glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine -platinum(II)]bis[diamine(chloro)platinum (II)]tetrachloride, diarizidinyl spermine,arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (seeWO 00/50032). A representative example of a hypoxia activatable compoundis tirapazamine. Proteasome inhibitors include, but are not limited to,lactacystin and bortezomib. Examples of microtubuleinhibitors/microtubule-stabilizing agents include paclitaxel, vindesinesulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol,rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide,anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, TDX258, the epothilones (see for exampleU.S. Pat. Nos. 6,284,781 and 6,288,237) and BMS188797. Representativeexamples of topoisomerase inhibitors include topotecan, hycaptamine,irinotecan, rubitecan, 6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo-[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H, 15H)dione,lurtotecan, 7-[2-(N -isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide, asulacrine, (5a, 5aB, 8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydrooxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexahydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis [(2-aminoethyl)amino]benzo[g]isoguinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1′-de] acridin-6-one, N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one, and dimesna. Examples of inhibitors ofmitotic kinesins, such as the human mitotic kinesin KSP, are describedin PCT Publications WO 01/30768 and WO 01/98278, WO 03/050,064 (Jun. 19,2003), WO 03/050,122 (Jun. 19, 2003), WO 03/049,527 (Jun. 19, 2003), WO03/049,679 (Jun. 19, 2003), WO 03/049,678 (Jun. 19, 2003) and WO03/39460 (May 15, 2003) and pending PCT Appl. Nos. US03/06403 (filedMar. 4, 2003), US03/15861 (filed May 19, 2003), US03/15810 (filed May19, 2003), US03/18482 (filed Jun. 12, 2003) and US03/18694 (filed Jun.12, 2003). In an embodiment inhibitors of mitotic kinesins include, butare not limited to inhibitors of KSP, inhibitors of MKLP1, inhibitors ofCENP-E, inhibitors of MCAK, inhibitors of Kif14, inhibitors of Mphosph1and inhibitors of Rab6-KIFL.

Inhibitors of kinases involved in mitotic progression include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK) (e.g., inhibitors of PLK-1), inhibitors of bub-1 andinhibitors of bub-R1. Antiproliferative agents include antisense RNA andDNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, andINX3001, and antimetabolites such as enocitabine, carmofur, tegafur,pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine,galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate,raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed,pemetrexed, nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycyl amino]-L-glycero-B-L-manno-heptopyranosyl]adenine, aplidine, ectein -ascidin, troxacitabine,4-[2-amino-4-oxo4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,1-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-yl acetic acid ester, swainsonine, lometrexol,dexrazoxane, methioninase, 2′-cyano -2′-deoxy-N4-palmitoyl-1-B-D-arabinofuranosyl cytosine and 3-aminopyridine-2-carboxaldehydethiosemicarbazone. Examples of monoclonal antibody targeted therapeuticagents include those therapeutic agents which have cytotoxic agents orradioisotopes attached to a cancer cell specific or target cell specificmonoclonal antibody. Examples include, for example, Bexxar. HMG-CoAreductase inhibitors are inhibitors of 3-hydroxy-3-methylglutaryl-CoAreductase. Compounds which have inhibitory activity for HMG-CoAreductase can be readily identified by using assays well-known in theart such as those described or cited in U.S. Pat. No. 4,231,938 and WO84/02131. Examples of HMG-CoA reductase inhibitors that may be usedinclude, but are not limited to, lovastatin (MEVACOR®; see U.S. Pat.Nos. 4,231,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S.Pat. Nos. 4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL®;see U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and5,180,589), fluvastatin (LESCOL®; see U.S. Pat. Nos. 5,354,772,4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896) andatorvastatin (LIPITOR®; see U.S. Pat. Nos. 5,273,995, 4,681,893,5,489,691 and 5,342,952). The structural formulas of these andadditional HMG-CoA reductase inhibitors that may be used in the instantmethods are described at page 87 of M. Yalpani, “Cholesterol LoweringDrugs”, Chemistry & Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos.4,782,084 and 4,885,314. In an embodiment, the HMG-CoA reductaseinhibitor is selected from lovastatin and simvastatin.

Prenyl-protein transferase inhibitors are compounds which inhibit anyone or any combination of the prenyl-protein transferase enzymes,including farnesyl-protein transferase (FPTase), geranylgeranyl -proteintransferase type I (GGPTase-I), and geranylgeranyl-protein transferasetype-II (GGPTase-II, also called Rab GGPTase). Examples ofprenyl-protein transferase inhibiting compounds include(±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)quinolinone,(−)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, 5(S)-n-butyl-1-(2,3-dimethylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,(S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl) methyl)-2-piperazinone,5(S)-n-butyl-1-(2-methylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]-2-piperazinone,1-(2,2-diphenylethyl)-3-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine,4-{-[4-hydroxymethyl-4-(4-chloropyridin-2-ylmethyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile,4-{-5-[4-hydroxymethyl-4-(3-chlorobenzyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-yl-methyl}benzonitrile,4-{3-[4-(2-oxo-2H-pyridin-1-yl)benzyl]-3H-imidazol-4-ylmethyl}-benzonitrile,4-{3-[4-(5-chloro-2-oxo-2H-[1,2′]bipyridin-5′-ylmethyl]-3H-imidazol-4-yl-methyl}benzonitrile,4-{3-[4-(2-oxo-2H-[1,2′]bipyridin-5′-ylmethyl]-3H-imidazol4-yl-methyl}benzonitrile,4-{3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl}benzonitrile,18,19-dihydro-19-oxo-5H,17H-6,10:12,16-dimetheno-1H-imidazo[4,3-c][1,11,4]dioxaazacyclo-nonadecine-9-carbonitrile,(±)-19,20-dihydro-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecine-9-carbonitrile,19,20-dihydro-19-oxo-5H, 17H-18,21-ethano-6,10:12,16-dimetheno-22H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile, and(+−)-19,20-dihydro-3-methyl-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]oxa-triazacyclooctadecine-9-carbonitrile.Other examples of prenyl-protein transferase inhibitors can be found inthe following publications and patents: WO 96/30343, WO 97/18813, WO97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO95/32987, U.S. Pat. Nos. 5,420,245, 5,523,430, 5,532,359, 5,510,510,5,589,485, 5,602,098, European Patent Publ. 0 618 221, European PatentPubl. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of aprenyl-protein transferase inhibitor on angiogenesis see European J. ofCancer 35(9): 1394-1401 (1999).

Angiogenesis inhibitors refers to compounds that inhibit the formationof new blood vessels, regardless of mechanism. Examples of angiogenesisinhibitors include, but are not limited to, tyrosine kinase inhibitors,such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) andFlk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived,or platelet derived growth factors, MMP (matrix metalloprotease)inhibitors, integrin blockers, interferon-.alpha., interleukin-12,pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidalanti-inflammatories (NSAIDs) like aspirin and ibuprofen as well asselective cyclooxygenase-2 inhibitors like celecoxib and rofecoxib (PNAS89:7384 (1992); JNCI 69:475 (1982); Arch. Ophthalmol. 108:573 (1990);Anat. Rec., (238):68 (1994); FEBS Letters 372:83 (1995); Clin, Orthop.313:76 (1995); J. Mol. Endocrinol. 16:107 (1996); Jpn. J. Pharmacol.75:105 (1997); Cancer Res. 57:1625 (1997); Cell 93:705 (1998); Intl. J.Mol. Med. 2:715 (1998); J. Biol. Chem. 274:9116 (1999)), steroidalanti-inflammatories (such as corticosteroids, mineralocorticoids,dexamethasone, prednisone, prednisolone, methylpred, betamethasone),carboxyamidotriazole, combretastatin A4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab.Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see, NatureBiotechnology, 17:963-968 (October 1999); Kim et al., Nature,362:841-844 (1993); WO 00/44777; and WO 00/61186). Other therapeuticagents that modulate or inhibit angiogenesis and may also be used incombination with the compounds of the instant invention include agentsthat modulate or inhibit the coagulation and fibrinolysis systems (seereview in Clin. Chem. La. Med. 38:679-692 (2000)). Examples of suchagents that modulate or inhibit the coagulation and fibrinolysispathways include, but are not limited to, heparin (see Thromb. Haemost.80:10-23 (1998)), low molecular weight heparins and carboxypeptidase Uinhibitors (also known as inhibitors of active thrombin activatablefibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101:329-354(2001)). TAFIa inhibitors have been described in PCT Publication WO03/013,526 and U.S. Ser. No. 60/349,925 (filed Jan. 18, 2002). Theinvention also encompasses combinations of the compounds of theinvention with NSAIDs which are selective COX-2 inhibitors (generallydefined as those which possess a specificity for inhibiting COX-2 overCOX-1 of at least 100 fold as measured by the ratio of IC₅₀ for COX-2over IC₅₀ for COX-1 evaluated by cell or microsomal assays). Suchcompounds include, but are not limited to those disclosed in U.S. Pat.No. 5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issuedJan. 19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat.No. 6,020,343, issued Feb. 1, 2000, U.S. Pat. No. 5,409,944, issued Apr.25, 1995, U.S. Pat. No. 5,436,265, issued Jul. 25, 1995, U.S. Pat. No.5,536,752, issued Jul. 16, 1996, U.S. Pat. No. 5,550,142, issued Aug.27, 1996, U.S. Pat. No. 5,604,260, issued Feb. 18, 1997, U.S. Pat. No.5,698,584, issued Dec. 16, 1997, U.S. Pat. No. 5,710,140, issued Jan.20, 1998, WO 94/15932, published Jul. 21, 1994, U.S. Pat. No. 5,344,991,issued Jun. 6, 1994, U.S. Pat. No. 5,134,142, issued Jul. 28, 1992, U.S.Pat. No. 5,380,738, issued Jan. 10, 1995, U.S. Pat. No. 5,393,790,issued Feb. 20, 1995, U.S. Pat. No. 5,466,823, issued Nov. 14, 1995,U.S. Pat. No. 5,633,272, issued May 27, 1997, and U.S. Pat. No.5,932,598, issued Aug. 3, 1999, all of which are hereby incorporated byreference. Representative inhibitors of COX-2 that are useful in themethods of the present invention include3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H) -furanone; and5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine.Compounds which are described as specific inhibitors of COX-2 and aretherefore useful in the present invention, and methods of synthesisthereof, can be found in the following patents, pending applications andpublications, which are herein incorporated by reference: WO 94/15932,published Jul. 21, 1994, U.S. Pat. No. 5,344,991, issued Jun. 6, 1994,U.S. Pat. No. 5,134,142, issued Jul. 28, 1992, U.S. Pat. No. 5,380,738,issued Jan. 10, 1995, U.S. Pat. No. 5,393,790, issued Feb. 20, 1995,U.S. Pat. No. 5,466,823, issued Nov. 14, 1995, U.S. Pat. No. 5,633,272,issued May 27, 1997, U.S. Pat. No. 5,932,598, issued Aug. 3, 1999, U.S.Pat. No. 5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419,issued Jan. 19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999,U.S. Pat. No. 6,020,343, issued Feb. 1, 2000, U.S. Pat. No. 5,409,944,issued Apr. 25, 1995, U.S. Pat. No. 5,436,265, issued Jul. 25, 1995,U.S. Pat. No. 5,536,752, issued Jul. 16, 1996, U.S. Pat. No. 5,550,142,issued Aug. 27, 1996, U.S. Pat. No. 5,604,260, issued Feb. 18, 1997,U.S. Pat. No. 5,698,584, issued Dec. 16, 1997, and U.S. Pat. No.5,710,140, issued Jan. 20, 1998. Other examples of angiogenesisinhibitors include, but are not limited to, endostatin, ukrain,ranpirnase, IM862,5-methoxy4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfatedmannopentanose phosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

Agents that interfere with cell cycle checkpoints are compounds thatinhibit protein kinases that transduce cell cycle checkpoint signals,thereby sensitizing the cancer cell to DNA damaging agents. Such agentsinclude inhibitors of ATR, ATM, the Chk1 and Chk2 kinases and cdk andcdc kinase inhibitors and are specifically exemplified by7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

Inhibitors of cell proliferation and survival signaling pathway arepharmaceutical agents that inhibit cell surface receptors and signaltransduction cascades downstream of those surface receptors. Such agentsinclude inhibitors of inhibitors of EGFR (for example gefitinib anderlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors ofIGFR, inhibitors of cytokine receptors, inhibitors of MET, inhibitors ofPI3K (for example LY294002), serine/threonine kinases (including but notlimited to inhibitors of Akt such as described in WO 02/083064, WO02/083139, WO 02/083140 and WO 02/083138), inhibitors of Raf kinase (forexample BAY-43-9006), inhibitors of MEK (for example CI-1040 andPD-098059) and inhibitors of mTOR (for example, rapamycin, everolimusand Wyeth CCI-779). Such agents include small molecule inhibitorcompounds and antibody antagonists.

Apoptosis inducing agents include activators of TNF receptor familymembers (including the TRAIL receptors).

In certain presently preferred embodiments of the invention,representative agents useful in combination with the compounds of theinvention for the treatment of cancer include, for example, irinotecan,topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin,cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids,imatinib (Gleevec™), nilotinib (Tasigna™), everolimus (Afinitor™),anthracyclines, rituximab, trastuzumab, as well as other cancerchemotherapeutic agents.

The above compounds to be employed in combination with the compounds ofthe invention will be used in therapeutic amounts as indicated in thePhysicians' Desk Reference (PDR) 47th Edition (1993), which isincorporated herein by reference, or such therapeutically useful amountsas would be known to one of ordinary skill in the art.

The compounds of the invention and the other anticancer agents can beadministered at the recommended maximum clinical dosage or at lowerdoses. Dosage levels of the active compounds in the compositions of theinvention may be varied so as to obtain a desired therapeutic responsedepending on the route of administration, severity of the disease andthe response of the patient. The combination can be administered asseparate compositions or as a single dosage form containing both agents.When administered as a combination, the therapeutic agents can beformulated as separate compositions, which are given at the same time ordifferent times, or the therapeutic agents, can be given as a singlecomposition.

Antiestrogens, such as tamoxifen, inhibit breast cancer growth throughinduction of cell cycle arrest, effecting the action of the cell cycleinhibitor p27Kip. Recently, it has been shown that activation of theRas-Raf-MAP Kinase pathway alters the phosphorylation status of p27Kipsuch that its inhibitory activity in arresting the cell cycle isattenuated, thereby contributing to antiestrogen resistance (Donovan etal., J. Biol. Chem. 276:40888, 2001). As reported by Donovan et al.,inhibition of MAPK signaling through treatment with MEK inhibitorchanged the phosphorylation status of p27 in hormone refactory breastcancer cell lines and in so doing restored hormone sensitivity.Accordingly, in one aspect, the compounds of formulas (I), (Ia), (II),(III) and (IV) may be used in the treatment of hormone dependentcancers, such as breast and prostate cancers, to reverse hormoneresistance commonly seen in these cancers with conventional anticanceragents.

In hematological cancers, such as chronic myelogenous leukemia (CML),chromosomal translocation is responsible for the constitutivelyactivated BCR-AB1 tyrosine kinase. The afflicted patients are responsiveto Gleevec, a small molecule tyrosine kinase inhibitor, as a result ofinhibition of Ab1 kinase activity. However, many patients with advancedstage disease respond to Gleevec initially, but then relapse later dueto resistance-conferring mutations in the Ab1 kinase domain. In vitrostudies have demonstrated that BCR-Av1 employs the Raf kinase pathway toelicit its effects. In addition, inhibiting more than one kinase in thesame pathway provides additional protection againstresistance-conferring mutations. Accordingly, in another aspect of theinvention, the compounds of formulas (I), (Ia), (II), (III) and (IV) areused in combination with at least one additional agent, such as Gleevec™or Tasigna™ in the treatment of hematological cancers, such as chronicmyelogenous leukemia (CML), to reverse or prevent resistance to the atleast one additional agent.

In another aspect, the present invention relates to methods ofinhibiting at least one serine/threonine kinase in the Jak/Statsignaling pathway in a subject, or treating a biological conditionmediated by a PKC signaling pathway in a subject, comprisingadministering a therapeutic composition comprising at least one compoundof formula (I), (Ia), (II) or (III) effective to inhibit the activity ofthe at least one serine/threonine kinase in the PKC signaling pathway inthe subject.

The therapeutic compositions in accordance with this aspect of theinvention are useful for treating patients with a need for suchinhibitors (e.g., those suffering from cancer mediated by abnormal PKCsignaling). Cancer types mediated by abnormal PKC signaling include, forexample, melanoma, uveal melanoma, lymphoma, diffuse large B-celllymphoma (DLBCL) and ibrutinib resistant cancers, papillary cancer,thyroid cancer, ovarian cancer, colon cancer, pancreatic cancer,non-small cell lung cancer (NSCLC), hematological cancers, chronicmyelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), andacute myeloid leukemia.

In one embodiment, the invention provides a method of inhibiting PKCα,PKCθ and GSKβ in a human or animal subject. The method includesadministering an effective amount of a compound, or a pharmaceuticallyacceptable salt thereof, of any of the embodiments of compounds offormula (I), (Ia), (II) or (III) to a subject in need thereof.

The present invention will be understood more readily by reference tothe following examples, which are provided by way of illustration andare not intended to be limiting of the present invention.

Representative side chains for use in the compounds of the followingexamples may generally be prepared in accordance with the followingprocedures:

EXAMPLES

Referring to the examples that follow, compounds of the preferredembodiments were synthesized using the methods described herein, orother methods, which are known in the art.

The compounds and/or intermediates were characterized by highperformance liquid chromatography (HPLC) using a Waters Milleniumchromatography system with a 2695 Separation Module (Milford, Mass.).The analytical columns were reversed phase Phenomenex Luna C18 −5μ,4.6×50 mm, from Alltech (Deerfield, Ill.). A gradient elution was used(flow 2.5 mL/min), typically starting with 5% acetonitrile/95% water andprogressing to 100% acetonitrile over a period of 10 minutes. Allsolvents contained 0.1% trifluoroacetic acid (TFA). Compounds weredetected by ultraviolet light (UV) absorption at either 220 or 254 nm.HPLC solvents were from Burdick and Jackson (Muskegan, Mich.), or FisherScientific (Pittsburgh, Pa.).

In some instances, purity was assessed by thin layer chromatography(TLC) using glass or plastic backed silica gel plates, such as, forexample, Baker-Flex Silica Gel 1B2-F flexible sheets. TLC results werereadily detected visually under ultraviolet light, or by employingwell-known iodine vapor and other various staining techniques.

The compounds and/or intermediates were characterized by LCMS. Generalconditions are as follows.

-   -   Low and High resolution Mass spectra were acquired on LC/MS        systems using electrospray ionization methods from a range of        instruments of the following configurations: Low        resolution—Agilent 1100 HPLC-UV system equipped with Waters ZQ        Mass Spectrometer and Schimadzu ELSD detectors; Low        resolution—Waters AcQuity UPLC-UV system equipped with Waters SQ        Mass Spectrometer and Thermo CAD detectors; High        resolution—Waters AcQuity UPLC-UV system equipped with a Waters        LCT Premier Mass Spectrometer. [M+H]⁺ refers to the protonated        molecular ion of the chemical species.        Analytical Instrument Methods        Low Resolution MS Methods    -   Agilent 1100 HPLC-UV with Waters ZQ Mass Spectrometer    -   Acidic Method: Column: Sunfire C18, 3×30 mm, 3.5 μm, temperature        40° C., 2 μL injection volume; Solvent A: 0.05% TFA in Water;        Solvent B: Acetonitrile; Gradient: 5-95%.    -   Basic Method: Column: Xbridge C18, 3×30 mm, 3.5 μm, temperature        40° C., 2 μL injection volume; Solvent A: 5 mM NH₄OH in water;        Solvent B: Acetonitrile; Gradient: 5-95%.        Low Resolution MS Method        Waters AcQuity equipped with Waters SQ Mass Spectrometer    -   Acidic Method: Column: Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μm,        temperature 50° C., 1.5 μL injection volume; Solvent A: 0.05%        TFA in Water; Solvent B: Acetonitrile; Gradient: 2-98% in 1.7        min.    -   Neutral Method: Column: Acquity BEH C18 1.7 μm 2.1×50 mm -50°        C.; Solvent A: Water+3.75 mM Amm Ace+2% CAN; Solvent B: ACN+3.75        mM Amm Ace+5% Water; Gradient: 2 to 98% B in 1.7 min—flow 1        mL/min.        HRMS Method        Waters AcQuity UPLC-UV Equipped with Waters LCT Premier Mass        Spectrometer    -   Acidic Method: Column: ACQUITY UPLC BEH C18, 130 Å, 1.7 um, 2.1        mm×50 mm—temp: 50° C.; Solvent A: WATER+0.1% Formic Acid;        Solvent B: Acetonitrile+0.1% Formic Acid; Gradient: 2-98%        Solvent B in 7.5 min; Scan speed: 0.2s, over range of 120-1100        Daltons    -   Basic Method: Column: ACQUITY UPLC BEH C18, 130 Å, 1.7 um, 2.1        mm×50 mm—temp: 50° C.; Solvent A: Water+5 mM NH₄OH; Solvent B: 5        mM NH₄OH in Acetonitrile; Gradient 2-98% in 7.5 min; Scan speed:        0.2s, over range of 120-1100 Daltons

Nuclear magnetic resonance (NMR) analysis was performed on

-   -   a Bruker 400 MHz NMR spectrometer using ICON-NMR, under TopSpin        program control. Spectra were measured at 298K, unless indicated        otherwise and were referenced relative to the solvent chemical        shift.

The purity of some of the compounds is assessed by elemental analysis(Desert Analytics, Tucson, Ariz.).

Melting points are determined on a Laboratory Devices Mel-Temp apparatus(Holliston, Mass.).

Preparative separations are carried out using

Waters 2545 HPLC System equipped with Waters PDA 2998 and/or Waters 3100Mass Spectrometer detection.

-   -   Acidic UV triggered: Water/Acetonitrile with 0.1% TFA modifier,        Flow rate 75 mL/min, 1.5 mL injection volume; Column: Waters        Sunfire 30 mm ID x 50 mm, 5 μm particle.    -   Basic UV triggered: Water/Acetonitrile with 5 mM NH₄OH, Flow        rate 75 mL/min, 1.5 mL injection volume; Column: Waters X-Bridge        30 mm ID x 50 mm, 5 μm particle        Methods:

All methods run a focused gradient from the starting % acetonitrile tothe final % acetonitrile over 3.5 minutes with a 10 second initial hold.After the gradient, all methods go to 95% acetonitrile over 30 secondsand hold there for 1.5 minutes before returning to the initialconditions. The Initial and Final conditions for each gradient are asfollows:

-   -   Method 0: 5-12% Acetonitrile    -   Method 1: 7.5-20% Acetonitrile    -   Method 2: 10-30% Acetonitrile    -   Method 3: 15-40% Acetonitrile    -   Method 4: 25-50% Acetonitrile    -   Method 5: 35-60% Acetonitrile    -   Method 6: 45-70% Acetonitrile    -   Method 7: 55-80% Acetonitrile    -   Method 8: 65-95% Acetonitrile

It should be understood that the organic compounds according to thepreferred embodiments may exhibit the phenomenon of tautomerism. As thechemical structures within this specification can only represent one ofthe possible tautomeric forms, it should be understood that thepreferred embodiments encompasses any tautomeric form of the drawnstructure.

It is understood that the invention is not limited to the embodimentsset forth herein for illustration, but embraces all such forms thereofas come within the scope of the above disclosure.

The examples below as well as throughout the application, the followingabbreviations have the following meanings. If not defined, the termshave their generally accepted meanings.

Abbreviations

DCM dichloromethane DIEA diisopropylethylamine DMA dimethylacetamideDMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMFN,N-dimethylformamide EtOAc ethyl acetate EtOH Ethanol MeCN acetonitrileMeOH methanol ACN acetonitrile BA bioavailability NBS N-bromosuccinimideNMP N-methyl-2-pyrrolidone RT or rt room temperature TDMSCltert-butyldimethylsilylchloride TEA triethylamine THF tetrahydrofuranRet. Time Retention time

-   -   MS Mass Spectra    -   HRMS High Resolution Mass Spectra    -   n-BuLi n-Butyllithium    -   DBAD Diisobutylazadicarboxylate    -   TFA Trifluoroacetic Acid    -   hr hour    -   g gram    -   L Liter    -   equiv equivalent    -   min minute    -   mmol millimole    -   NaHCO₃ sodium bicarbonate    -   N₂ nitrogen    -   MTBE methyl tertbutylether    -   mL milliliter    -   SiO₂ silica gel    -   NaH sodium hydride    -   TLC thin layer chromatography    -   KMnO₄ potassium permanganate    -   NH₄Cl ammonium chloride    -   HPLC High Performance Liquid Chromatography    -   AMRI Albany Molecular Research Inc    -   NH₄OH Ammonium Hydroxide    -   DIAD Diisopropylazadicarboxylate    -   HCl hydrochloric acid    -   DCE dichloroethane    -   NH₃ ammonia    -   HCOOH formic acid    -   Boc tert-butyl carboxylate    -   IPA isopropanol    -   mg milligram

Example 13-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

1) Synthesis of3-Amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylic Acid

Step 1. Synthesis of methyl3-amino-6-(trimethylstannyl)pyrazine-2-carboxylate

To a 500 mL two neck round-bottom flask equipped with a magnetic stirrerand a reflux condenser, methyl 3-amino-6-bromopyrazine-2-carboxylate (25g, 108 mmol) and Pd(PPh₃)₄ (6.23 g, 5.39 mmol) were suspended in1,2-dimethoxyethane (200 ml) at rt (room temperature) under an argonatmosphere. The mixture was degassed and flushed with Argon (two times)and hexamethylditin (29.0 mL, 140 mmol) was added via syringe through arubber septum, the mixture was degassed and flushed with argon again,and heated to 90° C. for 2 h. The mixture was cooled to rt andconcentrated in vacuo. Water (400 mL) and ethyl acetate (200 mL) wereadded, stirred for 20 minutes and filtered through celite. The filtratewas transferred to a separation funnel, the phases were separated andthe organic phase was washed with brine, dried over sodium sulfate andthe solvent was removed under reduced pressure. The residue was filteredover silica gel with heptane, then a solvent mixture of (ethyl acetate1:9 heptane) and finally a solvent mixture (ethyl acetate 2:8 heptane)which gave methyl 3-amino-6-(trimethylstannyl)pyrazine-2-carboxylate(20.92 g) of a yellow solid.

LC-MS (Basic Method): ret.time=1.07 min, M+H=317.8.

Step 2. Synthesis of methyl3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylate

In a 500 mL round-bottom flask equipped with a magnetic stirrer andargon inlet, methyl 3-amino-6-(trimethyl stannyl)pyrazine-2-carboxylate(20.92 g, 55.0 mmol), 2-Bromo-3-(trifluoromethyl) pyridine (14.38 g,60.5 mmol), Pd₂(dba)₃ (5.54 g, 6.05 mmol) and P(o-Tol)₃ (3.79 g, 12.09mmol) were dissolved in DMF (100 ml) at rt, followed by addition of NEt₃(10.72 ml, 77 mmol). The reaction mixture was heated to 110° C. underargon for 1 h. After cooling to rt, the reaction mixture was filteredthrough celite, washed with ethyl acetate and concentrated under reducedpressure. The residue was purified by silica gel chromatography usingethyl acetate heptane which gave methyl3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylate (7.8g) as a yellow solid.

LC-MS (Basic Method): ret.time=0.93 min, M+H=299.0.

Step 3. Synthesis of3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylic Acid

In a 250 mL round-bottom flask equipped with a magnetic stirrer, methyl3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylate (7.8g, 23.80 mmol) was dissolved in dioxane (100 mL) at rt. LiOH monohydrate(2.008 g, 47.6 mmol) was dissolved in water (25 ml) and added at rt andstirred for 1 h. The suspension was diluted with water (50 mL) andextracted with ethyl acetate (3×100 mL), the organic layer was backextracted with water (2×50 mL). The aqueous layer was adjusted to pH 3with conc. HCl and extracted with ethyl acetate (3×100 mL), the combinedorganic layers were dried over sodium sulfate, filtered and concentratedwhich gave3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylic acid(6.89 g) as a yellow powder. LC-MS (Basic method) M+H=284.9. ¹H-NMR(DMSO-d6): δ (ppm)=13.04(s broad, 0.84 H), 8.92 (d, 1H, J=4.9 Hz), 8.71(s, 1H), 8.33 (d, 1H, J=8.1 Hz), 7.70-7.67 (m, 3H).

2) Synthesis of3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Step 1. tert-butyl (1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate

To a 100 mL round-bottom flask equipped with a magnetic stirrer and anitrogen inlet, was added THF (20 mL), 3-fluoro-2-nitropyridine (1.524g, 10.73 mmol), tert-butyl piperidin-4-ylcarbamate (2.256 grams, 11.26mmol), N-ethyl-N-isopropylpropan-2-amine (3.47 g, 26.8 mmol). Themixture was heated to 70° C. for 24 hours. The mixture was cooled andconcentrated to a thick residue. The residue was purified by silica gelchromotography using ethyl acetate-heptane which gave tert-butyl(1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate (3.24 g, 98% yield).LC-MS (Basic method): ret.time=1.30 min, M+H=323.3

Step 2. tert-butyl (1-(2-aminopyridin-3-yl)piperidin-4-yl)carbamate

To a 250 mL round bottom flask equipped with a magnetic stirr bar purgedwith nitrogen was added tert-butyl(1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate (3.2 grams, 9.93 mmol),THF (75 ml) and Pd/C (1.1 g, 10% Pd on charcoal wet). The resultantmixture was stirred under an atmosphere of hydrogen until all tert-butyl(1-(2-aminopyridin-3-yl)piperidin-4-yl)carbamate was consumed. Thereaction was then purged with nitrogen, magnesium sulfate was added andstirred. The mixture was then filtered through a pad of celite. Thefilter pad was washed with excess DMC. The filtrate was concentrated toa thick residue which solidified under vacuum. The solid was dried to aconstant weight and used directly (2.9 grams, 99.9% yield).

LC-MS (Basic method): ret.time=1.04 min, M+H=293.

Step 3. Synthesis of tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate

To a 25 ml flask was added3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylic acid(332 mg, 1.168 mmol), DMF (4 ml),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (454 mg, 1.194 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.8 ml, 4.58 mmol). The mixture wasallowed to stir for about 5 minutes followed by the addition oftert-butyl (1-(2-aminopyridin-3-yl)piperidin-4-yl)carbamate (311 mg,1.064 mmol). The resultant mixture was allowed to stir over night. Theresidue was quenched with sat. NaCl solution (150 mL) and extracted withEtOAc (2×250 mL). The combined organic phases were dried over Na₂SO₄,filtrated and concentrated to a dark solid which was purified by silicagel chromatography using an ethyl acetate-heptane. LC-MS (Basic method):ret.time=1.22 min, M+H=559.

Step 4. Synthesis of3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

To a 100 mL flask was added a magnetic stirrer, tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate,and dichloromethane (10 mL). The mixture was stirred until all solidsdissolved and then cooled in an ice water bath under nitrogen. To thismixture was added trifluoroacetic acid (10 mL). The ice bath was removedand the mixture was stirred for 3 hours at RT. The mixture was thenconcentrated and the residue was then co-evaporated with toluene (20mL). The resultant residue was then mixed with brine (20 mL), saturatedwith NaHCO₃ and extracted with dichloromethane (3×50 mL). The combinedorganic phases were dried over Na₂SO₄, filtered and concentrated to asolid. The solid was dissolved in dichloromethane and precipitated withheptane. The solid was filtered and dried under vacuum to a constantweight which gave3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide(223 mg) in 95% yield. LC-MS (Basic Method): ret.time=1.1 min, M+H=459¹H NMR (400 MHz, Chloroform-d) δ 10.74 (s, 1H), 8.97-8.84 (m, 1H), 8.77(s, 1H), 8.30 (dd, J=5.2, 1.9 Hz, 1H), 8.20 (dd, J=8.0, 1.6 Hz, 1H),7.53 (dd, J=8.1, 4.8 Hz, 1H), 7.42 (dd, J=7.9, 1.7 Hz, 1H), 7.06 (dd,J=7.9, 4.9 Hz, 1H), 3.11 (dd, J=11.1, 4.9 Hz, 2H), 2.87-2.49 (m, 3H),1.45-1.14 (m, 3H).

Example 23-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridine-2-yl)pyrazine-2-carboxamide was prepared in a manner similar to Example1 (Method 1) where3-amino-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxylic acidwas used in place of3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylic acidwhich gave3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide(1.21 g) in 77% yield. LC-MS (Acidic Method): ret.time=1.12 min,M+H=475.2

¹H NMR (400 MHz, Methanol-d₄) δ 8.86 (s, 1H), 8.77 (dd, J=4.7, 1.4 Hz,1H), 8.14 (dd, J=5.0, 1.6 Hz, 1H), 8.05 (dp, J=8.5, 1.4 Hz, 1H),7.72-7.57 (m, 2H), 7.20 (dd, J=7.9, 4.9 Hz, 1H), 3.29 (s, 3H), 3.10 (dt,J=12.7, 4.0 Hz, 2H), 2.82-2.71 (m, 2H), 2.69-2.53 (m, 1H), 1.93-1.69 (m,2H), 1.37 (dtd, J=13.9, 10.5, 3.6 Hz, 2H).

Example 33-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Step 1: Synthesis of tert-butyl(4-(hydroxymethyl)-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate

To a 25 ml pear shaped flask was added 3-fluoro-2-nitropyridine, (0.441g, 3.1 mmol), tert-butyl (4-(hydroxymethyl)piperidin-4-yl)carbamate(0.65 g, 2.82 mmol), N-ethyl-N -isopropylpropan-2-amine, (0.839 g, 6.49mmol) and tetrahydrofuran (10 mL) and a magnetic stirrer. The mixturewas stirred under nitrogen and heated at 70° C. for 3 days. The mixturewas then cooled and concentrated to a thick residue and chromatographeddirectly on silica gel (ethyl acetate-heptane) which gave tert-butyl(4-(hydroxymethyl)-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate(0.668 g, 1.858 mmol) in 65.8% yield.

LC-MS (Basic method): ret.time=1.13 min, M+H=353.5.

Step 2: Synthesis of tert-butyl(4-(methoxymethyl)-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate

To a 25 mL pear shaped flask was added toluene (8 ml), dioxane (4 ml),tert-butyl(4-(hydroxymethyl)-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate(0.546 g, 1.549 mmol), dimethyl sulfate (0.293 g, 2.324 mmol), sodiumhydroxide (0.124 g, 1.549 mmol) and N,N,N -trimethyl-1,phenylmethanaminium chloride (0.288 g, 1.549 mmol). The resultantmixture was stirred for 18 hours. The reaction was diluted with 40 ml ofethyl acetate and stirred followed by the addition of a small amount(spoonful) of MgSO₄. The mixture was stirred for about 5 min., filteredand concentrated. The resultant residue was chromatographed on silicagel (ethyl acetate-heptane gradient 10-100%) which gave tert-butyl(4-(methoxymethyl)-1-(2-nitropyridin -3-yl)piperidin-4-yl)carbamate(0.556 g, 1.487 mmol) in 96% yield.

LC-MS (Basic Method): ret.time=1.44 min, M+H=367.4.

Step 3: Synthesis of tert-butyl(1-(2-aminopyridin-3-yl)-4-(methoxymethyl) piperidin-4-yl)carbamate

To a 100 mL round bottom flask was added tert-butyl(4-(methoxymethyl)-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate(0.697 g, 1.902 mmol), ethyl acetate (20 mL) and 10% palladium on carbonwet (about 0.7 g). The flask was purged with hydrogen and stirred undera balloon of hydrogen for 16 hrs. To the resultant mixture was thenadded MgSO₄ (5 grams) and stirred. The mixture was then filtered througha pad of MgSO₄ under a cone of nitrogen. The filtrate was concentratedto dryness which gave tert-butyl(1-(2-aminopyridin-3-yl)-4-(methoxymethyl)piperidin-4-yl)carbamate(0.454 g, 1.322 mmol) in 98% yield.

LC-MS (Basic Method): ret.time=0.88 min, M+H=337.5.

Step 4: Synthesis of tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-(methoxymethyl)piperidin-4-yl)carbamate

To a 25 mL flask was added3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylic acid(0.188 g, 0.66 mmoles), DMF (2 ml),2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate (HBTU), (0.25 g, 0.66 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.18 ml, 0.99 mmol. The mixture was allowed tostir for about 60 minutes followed by the addition of tert-butyl(1-(2-aminopyridin-3-yl)-4-(methoxymethyl)piperidin-4-yl)carbamate(0.111 g, 0.33 mmol). The resultant mixture was allowed to stir for 18hours and then concentrated to a thick residue. The residue waschromatographed directly on silica gel using ethyl acetate and heptanewhich gave tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-(methoxymethyl)piperidin-4-yl)carbamate(0.432 g).

LC-MS (Basic method): ret.time=1.12 min, M+H=603.4.

Step 5: Synthesis of3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl) pyridine-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

To a 100 ml flask was added a magnetic stirrer, tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate(0.199 g, 0.33 mmol) and dichloromethane (10 mL). The mixture wasstirred until all solids dissolved and then cooled in an ice water bathunder nitrogen. To this mixture was added trifluoroacetic acid (25 mL).The ice bath was removed and the mixture was stirred for 3 hours at roomtemperature. The mixture was then concentrated and the residue was thenco-evaporated with toluene (30 mL) 3 times to a thick residue. Theresidue was purified by reverse phase HPLC (method 3) which gave3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide(0.142 g, 0.277 mmol) in 84% yield. LC-MS (Basic method): ret.time=1.04min, M+H=503.2. ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 9.00 (dd,J=4.8, 1.5 Hz, 1H), 8.45 (dd, J=8.1, 1.4 Hz, 1H), 8.11 (dd, J=4.8, 1.6Hz, 3H), 7.78 (dd, J=8.0, 4.8 Hz, 1H), 7.55 (dd, J=8.1, 1.8 Hz, 1H),7.16 (dd, J=7.9, 4.8 Hz, 1H), 3.13 (s, 3H), 2.92 (dt, J=11.0, 7.1 Hz,2H), 2.68 (dt, J=11.2, 3.4 Hz, 2H), 1.38-1.00 (m, 9H), 0.94-0.77 (m,1H).

Example 43-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide

Synthesis of3-amino-6-(3-morpholinoisoquinolin-1-yl)pyrazine-2-carboxylic acid

Step 1. Synthesis of methyl3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxylate

In a 500 mL round-bottom flask equipped with a magnetic stirrer, asolution of methyl 3-amino-6-bromopyrazine-2-carboxylate (10 g, 43.1mmol), bis(pinacolato)diboron (13.68 g, 53.9 mmol), KOAc (7.61 g, 78mmol) and PdCl₂(dppf) (79 mg, 0.108 mmol) in dioxane (200 mL) wasdegassed and flushed with nitrogen (two times), and then was heated at80° C. for 3 hr. The reaction mixture was cooled to 25° C. and added 30mL of DCM and filtered through celite. The filtrate was added 60 mL ofheptane. The suspension was concentrated to ½ volume, and filtered. Thesolid was washed with heptane (3×20 mL) and dried under vacuum whichgave methyl3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxylate(12.85 g, 46.0 mmol).

LC-MS (acidic method)::ret.time=1.04 min, M+H=198.1

Step 2. Synthesis of methyl3-amino-6-(3-morpholinoisoquinolin-1-yl)pyrazine-2-carboxylate

In a 15 mL round-bottom flask equipped with a magnetic stirrer, asolution of 4-(1-chloroisoquinolin-3-yl)morpholine (673 mg, 2.412 mmol),methyl3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxylate(673 mg, 2.412 mmol), K₃PO₄ (3.02 ml, 3.02 mmol, 1M) and PdCl₂(dppf)(118 mg, 0.161 mmol) in dioxane (12 mL) was degassed and flushed withnitrogen (two times). The mixture was heated at 85° C. for 3 hr. Thereaction was cooled to rt, and added water (100 mL) and extracted withEtOAc (3×50 mL), dried over Na₂SO₄ and concentrated. The crude productwas purification by acidic HPLC column (Method 4) which gave methyl3-amino-6-(3morpholinoisoquinolin-1-yl)pyrazine-2-carboxylate (460 mg,1.259 mmol) in 62% yield.

LC-MS (acidic method)::ret.time=1.39 min, M+H=366.4.

Step 3. Synthesis of3-amino-6-(3-morpholinoisoquinolin-1-yl)pyrazine-2-carboxylic acid

In a 100 mL round-bottom flask equipped with a magnetic stirrer, asolution of methyl3-amino-6-(3morpholinoisoquinolin-1-yl)pyrazine-2-carboxylate (460 mg,1.259 mmol) in THF (4 mL) and MeOH (4.00 mL) was added LiOH.H₂O (3.15mL, 6.29 mmol) in water (4 mL) and stirred for 25° C. for 2 hr. Thereaction mixture was concentrated. Then was added 5 mL of water andacidified with 0.5N HCl to pH 5. The reaction mixture was filtered andwashed with water (3×20 mL), and dried, which provided3-amino-6-(3-morpholinoisoquinolin-1-yl)pyrazine-2-carboxylic acid (377mg, 1.073 mmol) in 85% yield. LC-MS (acidic method)::ret.time=1.02 min,M+H=352.4.

Step 4. Synthesis3-amino-N-(3-(4-methyl-4-pivalamidopiperidin-1-yl)pyridin-2-yl)-6-(3-morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide

In a 100 mL round-bottom flask equipped with a magnetic stirrer, asolution of3-amino-6-(3-morpholinoisoquinolin-1-yl)pyrazine-2-carboxylic acid inDMF (3 mL) was added DIEA (0.149 mL, 0.854 mmol) and HATU (156 mg, 0.410mmol), followed tert-butyl(1-(2-aminopyridin-3-yl)-4-methylpiperidin-4-yl)carbamate (105 mg, 0.342mmol) and was stirred at 25° C. for 60 hr. The reaction mixture wasadded 80 mL of water and extracted with EtOAc (3×40 mL), dried overNa₂SO₄ and concentrated. The crude product was purified by basic HPLC(Method 3) which gave3-amino-N-(3-(4-methyl-4-pivalamidopiperidin-1-yl)pyridin-2-yl)-6-(3-morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide(108 mg, 0.169 mmol) in 49% yield.

LC-MS (acidic method)::ret.time=2.30 min, M+H=640.7.

Step 5. Synthesis3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide

In a 100 mL round-bottom flask equipped with a magnetic stirrer, TFA(0.650 mL, 8.44 mmol) was cooled at −20° C., was added a solution of3-amino-N-(3-(4-methyl-4-pivalamidopiperidin-1-yl)pyridin-2-yl)-6-(3-morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide(108 mg, 0.169 mmol) in DCM (0.18 mL) slowly. The reaction mixture wasstirred at 25° C. for 45 min. The reaction mixture was concentrated. Thecrude product was purified by basic HPLC (method 3) which gave3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide(33 mg, 0.058 mmol) in 34% yield. LC-MS (acidic method)::ret.time=1.22min, M+H=540.6. ¹H NMR (METHANOL-d₄) d: 8.89 (s, 1H), 8.47 (d, J=8.5 Hz,1H), 8.11 (dd, J=4.9, 1.6 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.47-7.64 (m,2H), 7.28 (ddd, J=8.5, 7.0, 1.1 Hz, 1H), 7.14 (dd, J=7.8, 5.0 Hz, 1H),7.03 (s, 1H), 3.82-3.91 (m, 4H), 3.56-3.65 (m, 4H), 2.69-2.80 (m, 2H),2.56-2.68 (m, 2H), 0.79-1.02 (m, 4H), 0.49 (br. s., 3H).

Example 53-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Synthesis of tert-butyl (1-(2-aminopyridin-3-yl)-4-(((tertbutyldimethylsilyl)oxy) methyl) piperidin-4-yl)carbamate

Step 1. Synthesis of tert-butyl(4-(hydroxymethyl)-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate

To a 25 mL round bottom flask was combined 3-fluoro-2-nitropyridine(0.441 g, 3.1 mmol), tert-butyl(4-(hydroxymethyl)piperidin-4-yl)carbamate (0.65 g, 2.82 mmol),N-ethyl-N -isopropylpropan-2-amine (1.2 mL) and THF (10 mL). The mixturewas heated to 70° C. for 48 hrs. The mixture was cooled and concentratedto a thick residue. The residue was purified by silica gelchromotography using ethyl acetate and heptane which gave tert-butyl(4-(hydroxymethyl)-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate(0.668 g) in 98% yield.

LC-MS (Basic method): ret.time=1.13 min, M+H=353.5.

Step 2. Synthesis of tert-butyl(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate

To a 50 mL round bottom flask was combined tert-butyl(4-(hydroxymethyl)-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate (1.08g, 3.06 mmol), DMF (10 mL) and imidazole (0.459 g, 6.74 mmol) followedby tert-butylchlorodimethylsilane (0.554 g, 3.68 mmol). The mixture wasallowed to stir until all alcohol was converted to the silyl ether. Themixture was then concentrated and chromatographed on silica gel usingethyl acetate and heptane which gavetert-butyl(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate(1.178 g) in 99% yield. LC-MS (Basic method): ret.time=1.84 min,M+H=467.3

Step 3. Synthesis of tert-butyl (1-(2-aminopyridin-3-yl)-4-(((tertbutyldimethylsilyl)oxy) methyl) piperidin-4-yl)carbamate

Starting with tert-butyl(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate(1.178 g), the nitro compound was treated with hydrogen and palladium asdescribed in example 1 which gave tert-butyl(1-(2-aminopyridin-3-yl)-4-(((tert butyldimethylsilyl)oxy) methyl)piperidin-4-yl)carbamate (0.954 g) in 85% yield.

LC-MS (Basic method): ret.time=1.78 min, M+H=437.3

Step 4. Synthesis of tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-4-yl)carbamate

Starting with tert-butyl (1-(2-aminopyridin-3-yl)-4-(((tertbutyldimethylsilyl)oxy) methyl) piperidin-4-yl)carbamate (0.2 g, 0.459mmol), tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-4-yl)carbamate was prepared asdescribed in example 1 and used directly.

Step 5. Synthesis of3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

The tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-4-yl)carbamate from step 4 was treated with trifluoroaceticacid in a manner as described in example 1 which gave3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide(0.108 g, 0.217 mmol) in 21% yield. LC-MS (Basic method): ret.time=0.92min, M+H=489.2. ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 8.97 (dd,J=4.8, 1.5 Hz, 1H), 8.77 (s, 1H), 8.39 (dd, J=8.2, 1.5 Hz, 1H),8.26-7.65 (m, 4H), 7.56 (dd, J=8.2, 1.9 Hz, 1H), 7.16 (dd, J=7.9, 4.7Hz, 1H), 4.34 (s, 1H), 3.23-3.07 (m, 3H), 2.91 (td, J=10.6, 4.2 Hz, 2H),2.76-2.38 (m, 13H), 1.69-1.43 (m, 3H).

Example 63-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamidewas prepared in a manner as described for Example 1, Method 1 (0.0865 g)in 85% yield. LC-MS (acidic method): ret.time=1.24 min, M+H=505.2. ¹HNMR (DMSO-d6) δ: 10.75 (s, 1H), 8.92 (s, 1H), 8.77 (dd, J=4.6, 1.3 Hz,1H), 8.11 (dd, J=4.8, 1.6 Hz, 1H), 8.08 (br s, 1H), 8.06 (dt, J=8.4, 1.4Hz, 1H), 7.65 (dd, J=8.4, 4.6 Hz, 1H), 7.60 (dd, J=8.0, 1.7 Hz, 1H),7.17 (dd, J=7.8, 4.8 Hz, 1H), 4.48 (s, 1H), 2.97 (td, J=11.3, 3.0 Hz,2H), 2.75 (dq, J=7.6, 3.9 Hz, 4H), 1.77 (s, 2H), 1.47-1.16 (m, 4H).

Example 73-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Synthesis of tert-butyl(1-(2-(3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate

Step 1. Synthesis of tert-butyl(1-(2-(3-amino-6-bromopyrazine-2-carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate

In a 100 mL round-bottom flask equipped with a magnetic stirrer, asolution of 3-amino-6-bromopyrazine-2-carboxylic acid (1.044 g, 4.79mmol), tert-butyl (1-(2-aminopyridin-3-yl)piperidin-4-yl)carbamate (1.4g, 4.79 mmol), DIPEA (2.091 mL, 11.97 mmol) and HATU (2.185 g, 5.75mmol) in DMF (15 mL) was stirred at 25° C. for 15 hr. The reactionmixture was quenched with 30 mL water and extracted with EtOAc (3×20mL). The ethyl acetate wash was dried over Na₂SO₄ and concentrated. Thecrude product was purified by silica gel chromatography using ethylacetate and heptane which gave3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-bromopyrazine-2-carboxamide(1.76 g, 3.57 mmol) in 74% yield. LC-MS (acidic method)::ret.time=1.17min, M+H=492.3.

Step 2. Synthesis of tert-butyl(1-(2-(3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate

In a 15 seal round-bottom flask equipped with a magnetic stirrer, asolution of3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-bromopyrazine-2-carboxamide(220 mg, 0.447 mmol), bis(pinacolato)diboron (142 mg, 0.559 mmol), KOAc(79 mg, 0.804 mmol) and PdCl2(dppf) (16.35 mg, 0.022 mmol) in dioxane(2.5 mL) was degassed and flushed with nitrogen (two times), and washeated at 80° C. for 3 h. The reaction mixture was cooled to rt, dilutedwith 30 mL of DCM and filtered through celite. The filtrate was thendiluted with 60 mL of heptane, and then concentrated to ½ volume. Themixture was filtered, the solid was washed with heptane (3×20 mL) anddried under vacuum which gave tert-butyl(1-(2-(3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate(173 mg, 0.321 mmol) in 71% yield. LC-MS (acidic method)::ret.time=0.91min, M+H=458.4.

Step 3. Synthesis of tert-butyl(1-(2-(3-amino-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate

In a 15 mL round-bottom flask equipped with a magnetic stirrer, asolution of tert-butyl(1-(2-(3-amino-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate(316 mg, 0.497 mmol),4-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)morpholine (190 mg, 0.710mmol), K₃PO₄ (1M) (0.923 ml, 0.923 mmol) and PdCl₂(dppf) (41.6 mg, 0.057mmol). in dioxane (6 mL) was degassed and flushed with nitrogen (twotimes). After being stirred at 80° C. for 2 h., the reaction was cooledto rt. The reaction mixture was added to water (100 mL) and extractedwith EtOAc (3×50 mL), then dried over Na₂SO₄ and concentrated. The crudeproduct was purified by HPLC (acidic method 3) which gave tert-butyl(1-(2-(3-amino-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate(62 mg, 0.096 mmol) 13% yield.

LC-MS (acidic method): ret.time=1.18 min, M+H=645.7.

Step 4. Synthesis of3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

In a 100 mL round-bottom flask equipped with a magnetic stirrer, TFA(0.370 mL, 4.81 mmol) was cooled to −20° C., a solution of3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide(62 mg, 0.096 mmol) in DCM (2 mL) was added and was stirred at 25° C.for 45 min. The reaction mixture was concentrated. The crude product waspurification by HPLC (basic method 3) which gave3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide(26.3 mg, 0.048 mmol) in 50% yield.

LC-MS (acidic method): ret.time=1.03 min, M+H=545.6 (M+H). ¹H NMR(METHANOL-d₄) d: 8.89 (s, 1H), 8.76 (s, 1H), 8.12 (dd, J=4.9, 1.4 Hz,1H), 7.63 (dd, J=8.0, 1.5 Hz, 1H), 7.20 (dd, J=7.9, 4.9 Hz, 1H),3.89-4.02 (m, 4H), 3.78 (t, J=4.9 Hz, 4H), 3.07 (d, J=12.0 Hz, 2H),2.52-2.79 (m, 3H), 1.79 (d, J=10.8 Hz, 2H), 1.18-1.44 (m, 2H).

Example 83-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(2-morpholinothiazol-4-yl)pyrazine-2-carboxamide

Step 1: Synthesis of tert-butyl(1-(2-(3-amino-6-(2-morpholinothiazol-4-yl)pyrazine-2-carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate

To a 25 mL round bottom flask was added(5-amino-6-((3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)pyridin-2-yl)carbamoyl)pyrazin-2-yl)boronicacid (0.36 g, 0.787 mmol), 4-(4-chlorothiazol-2-yl)morpholine (0.161 g,0.787 mmol), Pd (dppe) dichloride (0.085 g, 0.116 mmol), potassiumphosphate 1 M (1 mL) and a magnetic stirrer. The resultant mixture wasdegassed with nitrogen and then placed in an 80° C. preheated oil bathand heated for 2 hours. The reaction was removed from heat, cooled andthen poured into 100 ml of dichloromethane. Magnesium sulfate was addedto dry the reaction, followed by filtration and concentration to a thickresidue. The residue was chromatographed on silica gel using ethylacetate and heptane which gave tert-butyl(1-(2-(3-amino-6-(2-morpholinothiazol-4-yl)pyrazine-2-carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate(0.187 g, 0.289 mmol) in 37% yield.

LC-MS (basic method): ret.time=1.30 min, M+H=582.5.

Step 2: Synthesis of3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(2-morpholinothiazol-4-yl)pyrazine-2-carboxamide

To a 100 mL flask was added a magnetic stirrer, tert-butyl(1-(2-(3-amino-6-(2-morpholinothiazol-4-yl)pyrazine-2-carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate(0.113 g, 0.194 mmol) and dichloromethane (5 mL). The mixture wasstirred until all solids dissolved and then cooled in an ice water bathunder nitrogen. To this mixture was added trifluoroacetic acid (15 mL).The ice bath was removed and the mixture was stirred for 3 hours at roomtemperature. The mixture was then concentrated and the residue was thenco-evaporated with toluene (30 mL) 3 times to a thick residue. Theresidue was purified by method 3, which gave3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(2-morpholinothiazol-4-yl)pyrazine-2-carboxamide(0.026 g, 0.052 mmol) in 27% yield.

LC-MS (Basic method): ret.time=1.16 min, M+H=482.6. ¹H NMR (400 MHz,Chloroform-d) δ 10.97 (s, 2H), 8.85 (s, 2H), 8.23 (d, J=4.8 Hz, 2H),7.36 (d, J=8.0 Hz, 3H), 7.22 (d, J=18.0 Hz, 4H), 7.03-6.95 (m, 3H),3.83-3.76 (m, 10H), 3.62 (s, OH), 3.53-3.45 (m, 10H), 3.08 (d, J=11.5Hz, 5H), 2.74 (s, 2H), 2.66 (t, J=11.8 Hz, 6H), 1.89 (d, J=12.7 Hz, 5H),1.54 (d, J=11.9 Hz, 6H), 1.46 (s, 8H), 1.18 (s, 5H).

Example 93-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Step 1: Synthesis of tert-butyl(4-methyl-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate

To a solution of 3-fluoro-2-nitropyridine (11.2 g, 81 mmol) in dioxane(200 mL) was added tert-butyl (4-methylpiperidin-4-yl)carbamate (26 g,121 mmol). Huenig's Base (28.3 mL, 162 mmol) was added and the mixturewas heated to 85° C. for 18 hrs. The reaction was cooled to RT andconcentrated to give a brown solid. The solids were washed with 200 mLof 4:1 heptane:EtOAc. Slurry was concentrated to half volume andfiltered to collect (26.2 g, 78 mmol, 96%) brown solid. LC-MS (AcidicMethod): ret.time=1.46 min, M+H=337.4

Step 2: Synthesis of tert-butyl(4-methyl-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate

To a solution of tert-butyl(4-methyl-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate (11.6 g, 37.2mmol) in ethyl acetate (200 mL). 10% Pd—C (3.48 g) was added and stirredunder H₂ balloon pressure at RT for 4 h. A small amount of MgSO₄ wasadded to the reaction and then the reaction mixture was filtered througha pad of cellite, then washed with ethyl acetate (100 mL) and thefiltrate was concentrated to afford a brown solid (8.54 g, 27.9 mmol,85%). LC-MS (Acidic Method): ret.time=0.91 min, M+H=307.4.

Step 3: Synthesis of tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate

To a solution of3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylic acid indimethyl formamide (125 mL) was added ((1H-benzo[d][1,2,3]triazol-1-yl)oxy) tris(dimethylamino) phosphonium hexafluorophosphate(V) (1.8 g, 4.24mmol) and 4-methylmorpholine (1 mL, 9.79 mmol). Reaction stirred at RTfor 40 minutes. Tert-butyl(1-(2-aminopyridin-3-yl)-4-methylpiperidin-4-yl) carbamate indimethylformamide (25 mL) was added and reaction stirred for 16 hrs atRT. The reaction mixture was diluted with EtOAc and was washed withNaHCO₃(aq) (3×200 mL) and brine (lx 200 mL). The organic phase was driedwith Na₂SO₄, filtered and concentrated. The crude product was taken upin acetonitrile (30 mL) and mixture was allowed to stand at RT for aperiod of time. Yellow solid collected by filtration (1.39 g, 74%).LC-MS (Acidic Method): ret.time=1.13 min, M+H=573.3.

Step 4: Synthesis of3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

A solution of tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(1.39 g, 2.06 mmol) in dichloromethane (10 mL) was cooled to 0° C.2,2,2-trifluoroacetic acid (2.4 ml, 31 mmol) was added dropwise to thesolution. The mixture was allowed to warm to 22° C. and stirred for 4hrs. Reaction mixture was concentrated to remove DCM and excess TFA. Ared oil was produced, which was taken up in 100 mL CHCl₃/IPA 3:1 andsaturated aq. NaHCO₃ was added to neutralize the solution. The mixturewas then stirred at 22° C. for 16 hrs. The mixture transferred toseparatory funnel and aqueous layers were washed with CHCl₃/IPA 3:1(3×100 mL). Combined organic phases were dried with Na₂SO₄, filtered andconcentrated to afford a yellow solid. The crude product wasrecrystallized from acetonitrile. A yellow solid was collected byfiltration (0.82 g, 83%). LC-MS (Acidic Method): ret.time=0.75 min,M+H=473.2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.92 (dd, J=5.1, 1.4 Hz, 1H),8.68 (s, 1H), 8.47-8.27 (m, 1H), 8.12 (dd, J=4.9, 1.6 Hz, 1H), 7.83-7.50(m, 2H), 7.18 (dd, J=7.9, 4.9 Hz, 1H), 3.02-2.65 (m, 4H), 1.54-1.24 (m,4H), 0.74 (s, 3H).

Example 103-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamidewas prepared in a manner as described for Example 1, Method 1 (1.41 g)in 77% yield. LC-MS (acidic method): ret.time=1.0 min, M+H=489.1 ¹H NMR(400 MHz, Methanol-d₄) δ 8.81 (s, 1H), 8.73 (dd, J=4.7, 1.3 Hz, 1H),8.13 (dd, J=4.9, 1.6 Hz, 1H), 8.01 (dp, J=8.4, 1.4 Hz, 1H), 7.75-7.54(m, 2H), 7.19 (dd, J=7.9, 4.9 Hz, 1H), 3.04-2.74 (m, 4H), 1.67-1.35 (m,4H), 0.82 (s, 3H).

Example 113-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-morpholino-5-(trifluoromethyl)pyrimidin-4-yl)pyrazine-2-carboxamide

Step 1: Synthesis of4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)morpholine

To a round bottom flask was added morpholine (0.897 g, 10.3 mmol), and asolution of dichloroethane-tert-butanol (1:1, 30 mL) stirred undernitrogen and cooled in an ice water bath. To this mixture was added zincchloride (5.45 g, 40 mmol) in one portion and stirred for 30 minutesfollowed by the addition of 2,4-dichloro-5-(trifluoromethyl)pyrimidine(2.17 g, 10 mmol). The resultant solution was stirred at ice water bathtemperature followed by the fast dropwise addition ofN-ethyl-N-isopropylpropan-2-amine. The reaction was kept stirred at icewater bath temperature for 2 hours and then allowed to warm to roomtemperature and stirred for an additional 18 hours. Poured reaction into200 mL of DCM, stirred and filtered. The filtrate was concentrated andchromatographed on silica gel using ethyl acetate heptane which yielded4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)morpholine (2.1 g, 7.61mmol) in 76% yield. LC-MS (basic method): ret.time=1.40 min, M+H=268.4.

Step 2: Synthesis of tert-butyl(1-(2-(3-amino-6-(2-morpholino-5-(trifluoromethyl) pyrimidin-4-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl) carbamate

To a 10 mL screw cap vial was added3-amino-6-(2-morpholino-5-(trifluoromethyl)pyrimidin-4-yl)pyrazine-2-carboxylicacid (0.104 g, 0.281 mmol), which was prepared in analogy to Example 4,DMF (2 ml), N-ethyl-N-isopropylpropan-2-amine (0.12 mL, 0.689 mmol) and2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (0.128 g, 0.337 mmol). The mixture was stirredfor 1 hour. To the resultant mixture was added tert-butyl(1-(2-aminopyridin-3-yl)-4-methylpiperidin-4-yl)carbamate (0.095 g,0.309 mmol) and was stirred for 20 hours. The reaction was concentratedand tert-butyl(1-(2-(3-amino-6-(2-morpholino-5-(trifluoromethyl)pyrimidin-4-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamatewas obtained in 14% yield and used directly. LC-MS (basic method):ret.time=1.46 min, M+H=659.4.

Step 3: Synthesis of3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-morpholino-5-(trifluoromethyl)pyrimidin-4-yl)pyrazine-2-carboxamide

To a 25 mL flask was added tert-butyl(1-(2-(3-amino-6-(2-morpholino-5-(trifluoromethyl)pyrimidin-4-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(0.185 g, 0.281 mmol) and dichloromethane (10 mL) which was then stirredand cooled in an ice water bath under nitrogen. To this resultantmixture was added trifluoroacetic acid (20 mL) and stirred and thenallowed to warm to room temperature. The mixture was stirred for two andone half hours. The mixture was then concentrated and then coevaporatedwith toluene (30 mL). This coevaporation was done three times. Themixture was then chromatographed by HPLC method 4. The resultant solidwas then triturated with hot water, allowed to cool. The solid materialobtained was filtered and dried to a constant weight which gave3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-morpholino-5-(trifluoromethyl)pyrimidin-4-yl)pyrazine-2-carboxamide(0.0104 g, 0.281 mmol) in 14% yield. LC-MS (basic method): ret.time=1.15min, M+H=559.4. 1H NMR (400 MHz, Chloroform-d) δ 10.55 (s, 1H), 8.84 (s,1H), 8.69 (s, 1H), 8.29 (dd, J=4.9, 1.6 Hz, 1H), 7.45 (dd, J=8.0, 1.7Hz, 1H), 7.32 (s, 0H), 7.10 (dd, J=7.8, 4.8 Hz, 1H), 5.64 (d, J=81.5 Hz,1H), 5.32 (s, 1H), 3.97 (t, J=4.8 Hz, 4H), 3.81 (t, J=4.7 Hz, 4H),3.06-2.75 (m, 4H), 1.61 (ddd, J=13.5, 9.3, 4.0 Hz, 2H), 1.42 (dt,J=13.3, 3.9 Hz, 2H), 1.26 (s, 4H), 0.97 (s, 3H), 0.94-0.76 (m, 1H).

Example 123-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-fluoro-2-methylquinazolin-4-yl)pyrazine-2-carboxamide

Step 1: tert-butyl(1-(2-(3-amino-6-(6-fluoro-2-methylquinazolin-4-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate

The mixture of tert-butyl(1-(2-(3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(293 mg, 0.529 mmol), (4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine(125 mg, 0.637 mmol) and K₃PO₄ (1591 μl, 1.591 mmol, 1M aq. solution) indioxane (2 mL) was degassed with N₂ stream for 10 min. Then PdCl₂(dppf)(19.41 mg, 0.027 mmol) was added. The reaction mixture was degassed for5 min and then was heated at 80° C. under N₂ atmosphere for 5 h. Thereaction mixture was cooled to RT and filtered through Celite pad andwashed with DCM. The filtrate was added water and DCM. The aqueous phasewas further extracted with DCM 2×. The combined DCM phases wereconcentrated under vacuum. The residue was dissolved in MeOH and severaldrops of water, then filtered. The resulting solution was then separatedwith prep-HPLC (C-18 column, 25-50% ACN/H₂O w/0.1% TFA). The desiredfractions were combined and then DCM and 2M Na₂CO₃ aq. Solution werefurther added to make aqueous phase pH 8. The aq. phase was extractedwith DCM 2×. The combined DCM phases were evaporated to provide 141 mg(69% yield) as tert-butyl(1-(2-(3-amino-6-(6-fluoro-2-methylquinazolin-4-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate.LC/MS: m/z M+H=588.6

Step 2:3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-fluoro-2-methylquinazolin-4-yl)pyrazine-2-carboxamide

To a solution of TFA (336 μL, 4.36 mmol) in DCM (1 mL) at 0° C. wasadded tert-butyl(1-(2-(3-amino-6-(6-fluoro-2-methylquinazolin-4-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(128 mg, 0.218 mmol) in DCM (2 mL). The reaction mixture wasconcentrated under vacuum. The residue was diluted with DCM and water,and then 2N Na₂CO₃ was added to achieve pH 12 of the aqueous phase. Thebasic aqueous phase was extracted by DCM 3×. The combined organic phaseswere concentrated. The residue was dissolved in MeOH/MeCN and thenseparated by prep-HPLC(C-18 column, 10-30% ACN/H₂O w/0.1% TFA). Thedesired fractions were combined and 2N Na₂CO₃ was added to achieve pH11. The resulting basic solution was extracted by DCM 3×. The combinedDCM phases were concentrated under vacuum, which provided 74 mg (70%yield)3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-fluoro-2-methylquinazolin-4-yl)pyrazine-2-carboxamide.LC/MS: m/z M+H=488.2 ¹H NMR (METHANOL-d₄) δ: 9.15 (s, 1H), 8.52 (dd,J=9.7, 2.9 Hz, 1H), 8.17 (dd, J=5.0, 1.5 Hz, 1H), 8.10 (dd, J=9.3, 5.3Hz, 1H), 7.87 (ddd, J=9.2, 8.2, 2.9 Hz, 1H), 7.68 (dd, J=7.9, 1.6 Hz,1H), 7.21 (dd, J=7.9, 4.9 Hz, 1H), 3.37 (s, 2H), 2.93 (s, 3H), 2.80-2.90(m, 2H), 2.68-2.78 (m, 2H), 0.98-1.07 (m, 2H), 0.87-0.97 (m, 2H), 0.42(s, 3H)

Example 133-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

1) Synthesis of3-amino-6-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylicacid

Step 1. Synthesis of methyl3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxylate

A mixture of methyl 3-amino-6-bromopyrazine-2-carboxylate (8.8 g, 38mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (9.6g, 38 mmol), and potassium acetate (11 g, 110 mmol) in dioxane (200 mL)was degassed and then added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.4 g, 1.9mmol). The resulting mixture was stirred and heated at 80° C. undernitrogen atmosphere for 15 h. Additional ore4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.9 g, 7.6mmol) was added and the reaction mixture was heated for another 3 h. thereaction mixture was cooled to room temperature and the mixture wasdiluted with dichloromethane and filtered through a pad of diatomaceousearth. The filtrate was concentrated at reduced pressure and purified bysilica gel chromatography with a gradient from 0%-10% methanol indichloromethane to afford the desired product as brown solid (9.5 g, 90%yield). LC-MS (acidic method) ret.time=0.42 min, M+H=198.1 (LC-MS acidicmethod).

Step 2. Synthesis of 2-bromo-4-methoxy-3-(trifluoromethyl)pyridine

A mixture of 2-bromo-4-chloro-3-(trifluoromethyl)pyridine (200 mg, 0.768mmol) and aqueous sodium hydroxide (6 N, 0.640 mL) in methanol (7 mL)was stirred at room temperature for 2 h. The mixture was extracted withethyl acetate (3×10 mL) and the combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo to obtain 165 mg, 84%yield) of a white powder. LC-MS (acidic method): ret.time=1.11 min,M+H=257.9.

Step 3. Synthesis of methyl3-amino-6-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylate

A solution of methyl3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxylate(180 mg, 0.645 mmol), 2-bromo-4-methoxy-3-(trifluoromethyl)pyridine (165mg, 0.645 mmol), and 1M potassium phosphate (0.838 mL, 0.838 mmol) intetrahydrofuran (4 mL) was degassed under vacuum for 10 min, and thenwas addedchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphen-yl)palladium(II) (25 mg, 0.032 mmol). The mixture was heated at 50° C. undernitrogen atmosphere for 3 h. The reaction was cooled to room temperatureand diluted with ethyl acetate. The aqueous layer was added sat.ammonium chloride and back extracted with more ethyl acetate. Thecombined organic solution was purified by silica gel chromatography witha gradient from 0%-100% ethyl acetate in heptane to afford the desiredproduct as white solid (14 mg, 7% yield). LC-MS (Acidic method):ret.time=0.92 min, M+H=329.3.

Step 4. Synthesis of3-amino-6-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylicacid

A mixture of methyl3-amino-6-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylate(14 mg, 0.043 mmol) and aqueous sodium hydroxide (6 N, 0.071 mL, 0.43mmol) in methanol (3 mL) was stirred at room temperature for 5 h. Thenit was heated at 60° C. for 1 h. Adjust pH to 5 by using conc. HCl. Thesolution was concentrated in vacuo to obtain a white powder. It was usedin the next step without further purification. LC-MS (acidic method):ret.time=0.81 min, M+H=315.0.

2) Synthesis of3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamideStep 1. Synthesis of tert-butyl(4-methyl-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate

A mixture of 3-fluoro-2-nitropyridine (550 mg, 3.87 mmol), tert-butyl(4-methylpiperidin-4-yl)carbamate (871 mg, 4.06 mmol), and triethylamine(1.61 ml, 11.6 mmol) in dioxane (10 mL) was heated to 100° C. for 6 h.The mixture was cooled and concentrated to a thick residue. The residuewas diluted with water and extracted with dichloromethane (3×20 mL). Thecombined organic layer was purified by silica gel chromatography with agradient from 0%-100% ethyl acetate in heptane to afford the desiredproduct as yellow solid (1.3 g, 100% yield). LC-MS (Basic Method):ret.time=1.28 min, M+H=337.2.

Step 2. Synthesis of tert-butyl(1-(2-aminopyridin-3-yl)-4-methylpiperidin-4-yl)carbamate

To a solution of tert-butyl(4-methyl-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate (550 mg, 1.64mmol) in ethanol (10 mL) was added Pd/C (17 mg, 10% Pd on charcoal wet).The resultant mixture was stirred under an atmosphere of hydrogen untilall tert-butyl (4-methyl-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamatewas consumed. The reaction was then purged with nitrogen. The mixturewas then filtered through a pad of celite. The filter pad was washedwith excess DMC. The filtrate was concentrated to a thick residue whichsolidified under vacuum. The solid was dried to a constant weight andused directly (500 mg, 100% yield). LC-MS (Basic Method): ret.time=0.78min, M+H=308.3.

Step 3. Synthesis of tert-butyl(1-(2-(3-amino-6-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate

A mixture of3-amino-6-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylicacid (14 mg, 0.043 mmol), tert-butyl(1-(2-aminopyridin-3-yl)-4-methylpiperidin-4-yl)carbamate (13 mg, 0.043mmol), N-ethyl-N-isopropylpropan-2-amine (0.019 mL, 0.11 mmol), and(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (COMU) (44 mg, 0.10 mmol) in dimethylformamide (0.4ml) was stirred under nitrogen atmosphere at room temperature for 60 h.The residue was concentrated to a dark solid which was purified by HPLC(Sunfire 30×50 mm 5 μm column ACN/H2O w/0.1% TFA 75 mL/min., 0.5 mLinjection) to afford a yellow solid (25 mg, 81% yield). LC-MS (BasicMethod): ret.time=1.18 min, M+H=603.2.

Step 4. Synthesis of3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

A mixture of tert-butyl(1-(2-(3-amino-6-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(25 mg, 0.041 mmol) and trifluoroacetic acid (0.32 mL, 4.2 mmol) indichloromethane (2 mL) was stirred at room temperature for 12 h. Theresultant residue was concentrated to a dark gum which was purified byHPLC (X-Bridge 30×50 mm 5 um column ACN/H₂O w/5 mM NH₄OH 75 mL/min. at 5mL injection) to afford a yellow solid (5 mg, 23% yield). LC-MS (Basicmethod): ret.time=0.79 min, M+H=502.9. ¹H NMR (400 MHz, METHANOL-d₄) δppm 8.70 (d, J=5.77 Hz, 1 H) 8.53 (s, 1 H) 8.11 (dd, J=5.02, 1.51 Hz, 1H) 7.67 (dd, J=7.91, 1.63 Hz, 1 H) 7.40 (d, J=5.77 Hz, 1 H) 7.16 (dd,J=7.91, 4.89 Hz, 1 H) 4.08 (s, 3 H) 2.85-3.00 (m, 2 H) 2.72-2.85 (m, 2H) 1.28-1.50 (m, 4 H) 0.81 (s, 3 H).

Example 143-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Step 1. Synthesis of tert-butyl(1-(2-(3-amino-6-bromopyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate

In a 100 mL round bottom flask equipped with a magnetic stirrer HBTU(2.23 gm, 5.87 mmol), 3-amino-6-bromopyrazine-2-carboxylic acid (1.17gm, 5.39 mmol), and N-ethyl-N-isopropylpropan-2-amine (1.28 mL, 7.34mmol) were allowed to stir in DMF (15 ml) for 15 minutes whereupontert-butyl (1-(2-aminopyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(1.5 gm, 4.9 mmol) was added in one portion. Reaction was allowed tostir for 16 hr. Reaction was then poured into DMF and extracted thricewith 50 mL ethyl acetate. Organic extracts were combined and dried withbrine followed by anhydrous sodium sulfate. The residue was purified bysilica gel using gradient chromotography ethanol—ethyl acetate 0-10%which yielded pure tert-butyl(1-(2-(3-amino-6-bromopyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(1.86 gm, 67.5% yield) upon evaporation of fractions containing thedesired product. LC-MS (Acidic method): ret.time=1.17 min, M+H=508.3.

Step 2. Synthesis of tert-butyl(1-(2-(3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate

In a 100 mL round-bottom flask equipped with a magnetic stirrertert-butyl(1-(2-(3-amino-6-bromopyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(1.9 gm, 3.7 mmol), bis(pinacolato)diboron (1 gm, 4 mmol) and potassiumacetate (0.54 gm, 5.5 mmol) were suspended in dioxane (15 mL). Theformed suspension was bubbled with nitrogen gas for minutes to removedissolved oxygen. 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.13 gm, 0.18 mmol) was then added and the reaction heated to 90°C. in an oil bath. After 3 hr volatiles were removed and the residuesuspended in ethyl acetate which was washed with water to remove excesspotassium acetate. The residue was dissolved into dichloromethane andtriturated with heptane until solids formed which were filtered andwashed with further portions of heptane to yield tert-butyl(1-(2-(3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(1.32 gm, 46% yield) as a brown powder of sufficient purity for furthertransformations. LC-MS (Acidic method): ret.time=0.91 min, M+H=554.4.

Step 3. Synthesis of2-chloro-6-(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)pyridine

In a 100 ml round bottom flask 2,6-dichloro-3-(trifluoromethyl)pyridine(1.25 gm, 5.79 mmol) was dissolved into DMF (30 mL) along with3,3-difluoroazetidine (0.75 gm, 5.79 mmol) andN-ethyl-N-isopropylpropan-2-amine (1.5 ml, 8.7 mmol). After 16 hr thereaction was cooled, poured into water and extracted three times with 50mL ethyl acetate. The combined organic layers were dried with brine andanhydrous sodium sulfate. Volatiles were removed and the residuepurified by silica gel using gradient chromotography of 0-60% ethylacetate in heptane to yield pure2-chloro-6-(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)pyridine (935mg, 53% yield). LC-MS (Acidic method): ret.time=1.56 min, M+H=273.3.

Step 4. Synthesis of tert-butyl(1-(2-(3-amino-6-(6-(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate

In a 10 ml round bottom flask tert-butyl(1-(2-(3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(159 mg, 0.23 mmol) was combined with2-chloro-6-(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)pyridine (50mg, 0.183 mmol) and dissolved into THF along with 1M aqueoustripotassium phosphate (0.3 ml, 0.3 mmol). Suspension was degassed byevacuating and purging with nitrogen three times then stirring undernitrogen for 15 minutes.1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) was addedand then the reaction mixture was heated with a pre-heated oil bath to50 C for 16 hr. The reaction volatiles were removed and the residuedissolved into DCM and filtered through celite. Volatiles were thenremoved and the residue purified by silica gel using gradientchromotography of 0-60% ethyl acetate in heptane to obtain pure desiredtert-butyl(1-(2-(3-amino-6-(6-(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(70 mg, 54% yield). LC-MS (Acidic method): ret.time=1.27 min, M+H=664.7.

Step 5. Synthesis of3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Into a 10 mL round bottom flask tert-butyl(1-(2-(3-amino-6-(6-(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamatewas dissolved into 1.5 mL dichloromethane and treated with2,2,2-trifluoroacetic acid (0.2 ml, 2.2 mmol). After 16 hours thereaction was treated with saturated sodium bicarbonate solution until pH9 was reached. A solid precipitate formed and slowly redissolved. Theorganic layer was separated then dried with brine, anhydrous sodiumsulfate and then evaporated. The residue was purified by silica gelusing gradient chromotography of 0-10% ethanol in ethylacetate to yieldpure3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide(49 mg, 78% yield). LC-MS (Acidic method): ret.time=0.88 min, M+H=564.2.¹H NMR (400 MHz, Methanol-d₄) δ 8.64 (s, 1H), 8.11 (dd, J=5.0, 1.5 Hz,1H), 8.03 (d, J=8.8 Hz, 1H), 7.65 (dd, J=7.9, 1.6 Hz, 1H), 7.17 (dd,J=7.9, 4.9 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H), 4.51 (t, J=12.0 Hz, 4H),2.99-2.74 (m, 4H), 1.52-1.33 (m, 4H), 0.81 (s, 3H).

Example 153-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Step 1. Synthesis of 2-chloro-6-cyclopropyl-3-(trifluoromethyl)pyridine

To a 100 mL round-bottom flask was added toluene (20 mL),2,6-dichloro-3-(trifluoromethyl)pyridine (3 g, 13.8 mmol),cyclopropylboronic acid (1.3 g, 15.3 mmol), tricyclohexyl phosphine(0.39 g, 1.4 mmol), tribasic potassium phosphate (3.2 g, 15.3 mmol) andwater (1 mL). Suspension was degassed by evacuating and purging withnitrogen three times then stirring under nitrogen for 15 minutes.Diacetoxypalladium (0.16 g, 0.7 mmol) was added and then the reactionmixture was heated with a pre-heated oil bath to 100° C. for 16 hours.After this time the reaction volatiles were removed, the residuedissolved into DCM, filtered and then purified by silica gel usinggradient chromotography of 0-60% ethyl acetate in heptane to obtain thepure desired product 2-chloro-6-cyclopropyl-3-(trifluoromethyl)pyridine(2 gm, 59% yield). LC-MS (Acidic method): ret.time=1.61 min, M+H=222.2

Step 2. Synthesis tert-butyl(1-(2-(3-amino-6-(6-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate

To a 10 mL round bottom flask equipped with a magnetic stirrer andpurged with nitrogen was added2-chloro-6-cyclopropyl-3-(trifluoromethyl)pyridine (50 mg, 0.23 mmol),dioxane (2 ml), tert-butyl(1-(2-(3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(156 mg, 0.23 mmol) and 1M aqueous tribasic potassium phosphate (0.29mL, 0.29 mmol). The resultant mixture was stirred under an atmosphere ofnitrogen in an oil bath at 90° C. until all2-chloro-6-cyclopropyl-3-(trifluoromethyl)pyridine was consumed (16 hr).The mixture was then cooled and filtered through a pad of celite. Thefilter pad was washed with excess methylene chloride. The combinedfiltrates were concentrated to a thick residue and purified by silicagel using gradient chromotography of 0-75% ethyl acetate in heptane toyield (50 mg, 34% yield). LC-MS (Acidic method): ret.time=1.31 min,M+H=613.2.

Step 3. Synthesis of3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

To a 10 mL flask was added tert-butyl(1-(2-(3-amino-6-(6-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate,dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (0.1 mL, 1.2mmol). After 16 hrs the reaction was treated with excess saturatedaqueous sodium bicarbonate solution until pH 9 was reached. The organiclayer was separated, then dried with brine and anhydrous sodium sulfate.The impure final compound was purified by silica gel using gradientchromotography of 0-10% ethanol in ethyl acetate to yield pure3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide(41 mg, 93% yield). LC-MS (Acidic method): ret.time=1.22 min, M+H=513.2.¹H NMR (400 MHz, Methanol-d₄) δ 8.63 (s, 1H), 8.14-8.09 (m, 2H), 7.64(dd, J=8.0, 1.6 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.17 (dd, J=7.9, 4.9Hz, 1H), 2.97-2.73 (m, 4H), 2.26 (ddd, J=7.7, 4.5, 2.5 Hz, 1H),1.45-1.31 (m, 4H), 1.17-1.12 (m, 4H), 0.75 (s, 3H).

Example 163-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Step 1. Synthesis of tert-butyl(1-(2-(3-amino-6-(6-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate

In a 40 mL vial equipped with a magnetic stirrer,2-chloro-6-methoxy-3-(trifluoromethyl)pyridine (J. Heterocyclic Chem.,28, 971 (1991)) (40 mg, 0.190 mmol), tert-butyl(1-(2-(3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(100 mg, 0.181 mmol), PdCl₂(dppf) (6.61 mg, 0.09 mmol) and potassiumphosphate (1M, 0.271 mL) were suspended in 1,4-dioxane (2 ml), degassedwith N₂ for 10 min. and heated to 90° C. for 4 h. The mixture was cooledto rt and EtOAc (20 mL) was added, filtered through Celite washing withEtOAc 920 ml), concentrated in vacuo. The solid was purified byreverse-phase high-pressure liquid chromatography using a method with a35-60% ACN 3.5 min gradient through an X-Bridge 30×50 mm 5 um columnACN/H₂O w 5 mM NH₄OH 75 mL/min., 5 mL injection 3 times which gave 50 mg(yellow solid). LC-MS (Acidic method): ret.time=1.17 min, M+H=603.7

Step 2. Synthesis of3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

In a 40 mL vial equipped with a magnetic stirrer, was added2,2,2-trifluoroacetic acid (64 mL, 0.830 mmol) to a solution oftert-butyl(1-(2-(3-amino-6-(6-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(50 mg, 0.083 mmol) in dichloromethane (5 mL) and allowed to stir for 30min. at ambient temperature. The reaction was concentrated in vacuo andneutralized to afford 40 mg of the title compound. LC-MS (Acidicmethod): ret.time=0.83 min, M+H=503.5. ¹H NMR (400 MHz, Methanol-d₄) δ8.77 (s, 1H), 8.24-8.10 (m, 2H), 7.67 (dd, J=8.0, 1.6 Hz, 1H), 7.21 (dd,J=7.9, 4.9 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.08 (s, 3H), 3.37 (s, 1H),2.94 (ddd, J=12.6, 9.9, 3.1 Hz, 2H), 2.84 (dt, J=12.0, 4.6 Hz, 2H), 1.51(ddd, J=13.6, 9.8, 4.1 Hz, 2H), 1.39 (dt, J=13.3, 3.8 Hz, 2H), 0.82 (s,3H).

Example 173-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Step 1. Synthesis of tert-butyl(4-ethyl-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate

To a microwave vial equipped with a magnetic stirrer was added3-fluoro-2-nitropyridine (205 mg, 1.44 mmol), tert-butylpiperidin-4-ylcarbamate (329 mg, 1.443 mmol),N-ethyl-N-isopropylpropan-2-amine (559 mg, 4.33 mmol) in ethanol (10mL). The mixture was heated in a Biotage microwave reactor at 100° C.for 30 minutes. The mixture was cooled and concentrated to a thickresidue. The residue was purified by silica gel chromatography (usingmethanol/dichloromethane as eluent) to give tert-butyl(4-ethyl-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate (337 mg, 67%yield). LC-MS (Basic method): ret.time=1.45 min, M+H=351.0

¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (dd, J=4.4, 1.3 Hz, 1H), 7.89 (dd,J=8.3, 1.4 Hz, 1H), 7.63 (dd, J=8.3, 4.4 Hz, 1H), 6.52 (s, 1H),3.02-2.91 (m, 4H), 2.18-2.06 (m, 2H), 1.62 (q, J=7.4 Hz, 2H), 1.43-1.31(m, 11H), 0.75 (t, J=7.4 Hz, 3H).

Step 2. Synthesis of tert-butyl(1-(2-aminopyridin-3-yl)-4-ethylpiperidin-4-yl)carbamate

To a round bottom flask equipped with a magnetic stirrer and purged withnitrogen was added tert-butyl(4-ethyl-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate (337 mg, 0.96mmol), ethanol (10 mL) and Pd/C (41 mg, 10% Pd on charcoal wet). Theresultant mixture was stirred under an atmosphere of hydrogen until alltert-butyl (4-ethyl-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate wasconsumed. The reaction was filtered through a pad of celite, then rinsedwith methanol and ethyl acetate. The filtrate was concentrated in vacuo,then the obtained residue was dissolved in dichloromethane and filteredthrough a short pad of magnesium sulfate. The filtrate was concentratedto obtain tert-butyl(1-(2-aminopyridin-3-yl)-4-ethylpiperidin-4-yl)carbamate, as a whitesolid (268 mg, 87% yield). LC-MS (Basic method): ret.time=1.32 min,M+H=321.1.

Step 3. Synthesis of tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-ethylpiperidin-4-yl)carbamate

To a 20 mL scintillation vial equipped with a magnetic stirrer was added3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylic acid(61 mg, 0.22 mmol), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumhexafluorophosphate (120 mg, 0.32 mmol),N-ethyl-N-isopropylpropan-2-amine (73 mg, 0.56 mmol) in DMF (2 mL). Themixture was allowed to stir for 5 minutes at rt followed by the additionof tert-butyl (1-(2-aminopyridin-3-yl)-4-ethylpiperidin-4-yl)carbamate(60 mg, 0.187 mmol). The resultant mixture was allowed to stir overnightat rt, after which it was filtered. The filtrate was concentrated, thenthe residue was purified by reverse-phase HPLC (35-60% ACN 3.5 mingradient, X-Bridge 30×50 mm 5 μm column ACN/H₂O w/5 mm NH4OH, 75mL/min., 4 injections at 1.5 mL/injection) to obtain tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-ethylpiperidin-4-yl)carbamate(81 mg, 66% yield). LC-MS (Basic method): ret.time=1.42 min, M+H=587.0.

Step 4. Synthesis of3-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

To a 20 mL scintillation vial equipped with a magnetic stir bar wasadded tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-ethylpiperidin-4-yl)carbamate(81 mg, 0.14 mmol) and 1,4-dioxane (1 ml). A 4N HCl/1,4-dioxane solution(0.69 mL, 2.76 mmol) was then added in a dropwise fashion. The resultantmixture was stirred at rt for 3 hours, at which point all tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-ethylpiperidin-4-yl)carbamatewas consumed. Acetonitrile was added to reaction mixture, then solid wasfiltered and rinsed with additional acetonitrile. The obtained solid wasdried on a lyophilizer to obtain3-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide(57 mg, 77% yield), as its hydrochloride salt. LC-MS (Acidic method):ret.time=0.83 min, M+H=487.2. ¹H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H),8.98 (dd, J=4.9, 1.5 Hz, 1H), 8.81 (s, 1H), 8.44 (dd, J=8.1, 1.5 Hz,1H), 8.20 (dd, J=5.1, 1.5 Hz, 1H), 8.08 (s, 5H), 7.81-7.71 (m, 2H), 7.33(dd, J=7.9, 5.1 Hz, 1H), 3.17-3.07 (m, 2H), 2.93-2.84 (m, 2H), 1.68-1.58(m, 2H), 1.35-1.26 (m, 2H), 1.06 (q, J=7.5 Hz, 2H), 0.53 (t, J=7.5 Hz,3H).

Example 183-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-chloropyridin-2-yl)pyrazine-2-carboxamide

Step 1. Synthesis of methyl3-amino-6-(3-chloropyridin-2-yl)pyrazine-2-carboxylate

In a round-bottom flask equipped with a magnetic stirrer and nitrogeninlet was charged methyl3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxylate(906 mg, 3.25 mmol), 2-bromo-3-chloropyridine (500 mg, 2.6 mmol),PdCl₂(dppf) DCM (149 mg, 0.18 mmol), potassium phosphate (3.6 ml, 3.6mmol, 1M aq.) and THF (10 ml). The reaction was degassed with nitrogenfor 5 minutes, then mixture was heated to 55° C. under nitrogen for 16h. After cooling to rt, reaction mixture was diluted with ethyl acetate,then layers were allowed to separate. Organic layer was dried withsodium sulfate, dried and concentrated. The obtained residue waspurified by silica gel chromatography (using gradient ethylacetate/heptane 30-70% as eluent) to obtain methyl3-amino-6-(3-chloropyridin-2-yl)pyrazine-2-carboxylate (191 mg). Due tolow purity of product, it was therefore repurified by reverse-phase HPLC(15-40% ACN 3.5 min. gradient, X-Bridge 30×50 mm 5 μm column ACN/H₂O w/5mm NH₄OH, 75 mL/min., 2 injections at 1.5 mL/injection) to obtain methyl3-amino-6-(3-chloropyridin-2-yl)pyrazine-2-carboxylate (91 mg, 13%yield). LC-MS (Basic method): ret.time=0.92 min, M+H=265.0.

Step 2. Synthesis of methyl3-amino-6-(3-chloropyridin-2-yl)pyrazine-2-carboxylate

In a round-bottom flask equipped with a magnetic stirrer, methyl3-amino-6-(3-chloropyridin-2-yl)pyrazine-2-carboxylate (91 mg, 0.34mMoles) was dissolved in methanol (4 ml) at rt. Lithium hydroxide (0.52mL, 1.03 mmol, 2N aq.) and added at rt and stirred for 16 h. Volatileswere removed in vacuo, then the aqueous residue was acidified with 2Naq. HCl until pH 2 was attained.

The obtained precipitate was filtered and rinsed with water, then driedon lyophilizer to afford methyl3-amino-6-(3-chloropyridin-2-yl)pyrazine-2-carboxylate (77 mg, 89%yield), as a pale yellow solid. LC-MS (Acidic method): ret.time=0.68min, M+H=251.4.

Step 3. Synthesis of tert-butyl(1-(2-(3-amino-6-(3-chloropyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate

To a 20 mL scintillation vial equipped with a magnetic stir bar wasadded methyl 3-amino-6-(3-chloropyridin-2-yl)pyrazine-2-carboxylate (38mg, 0.15 mmol), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumhexafluorophosphate (84 mg, 0.22 mmol),N-ethyl-N-isopropylpropan-2-amine (51 mg, 0.39 mmol) in DMF (1.5 mL).The mixture was allowed to stir for 5 minutes at rt followed by theaddition of tert-butyl(1-(2-aminopyridin-3-yl)-4-methylpiperidin-4-yl)carbamate (40 mg, 0.13mmol). The resultant mixture was allowed to stir overnight at rt, afterwhich it was filtered. The filtrate was concentrated, then the residuewas purified by reverse-phase HPLC (35-60% ACN 3.5 min gradient,X-Bridge 30×50 mm 5 μm column ACN/H₂O w/5 mL NH₄OH, 75 mL/min., 3injections at 1.5 mL/injection) to obtain tert-butyl(1-(2-(3-amino-6-(3-chloropyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(46 mg, 65% yield), LC-MS (Basic method): ret.time=1.35 min, M+H=538.9.

Step 4. Synthesis of3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-chloropyridin-2-yl)pyrazine-2-carboxamide

To a 20 mL scintillation vial equipped with a magnetic stir bar wasadded tert-butyl(1-(2-(3-amino-6-(3-chloropyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(46 mg, 0.085 mmol) and dichloromethane (1 mL). Trifluoroacetic acid(146 mg, 1.28 mmol) was then added in a dropwise fashion. The resultantmixture was stirred at rt for 16 hours, at which point all tert-butyl(1-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-ethylpiperidin-4-yl)carbamatewas consumed. Reaction mixture was concentrated, then dichloromethaneand 2N aqueous sodium carbonate solution were added to the obtainedresidue in two phases. The organic and aqueous phases (layers) wereseparated. Organic layer was washed once with additional 2N aqueoussodium carbonate solution, then dried with sodium sulfate, filtered andconcentrated. Crude mixture was purified by reverse-phase HPLC (25-50%ACN 3.5 min gradient, X-Bridge 30×50 mm 5 μm column ACN/H₂O w/5 mmNH₄OH, 75 mL/min., 2 injections at 1.5 mLinjection) to obtain3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-chloropyridin-2-yl)pyrazine-2-carboxamide(25 mg, 67% yield), LC-MS (Acidic method): ret.time=0.75 min, M+H=439.0.¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 8.77 (s, 1H), 8.67 (dd,J=4.7, 1.5 Hz, 1H), 8.14-8.06 (m, 2H), 7.59 (dd, J=7.9, 1.7 Hz, 1H),7.52 (dd, J=8.2, 4.6 Hz, 1H), 7.15 (dd, J=7.9, 4.8 Hz, 1H), 2.97-2.88(m, 2H), 2.77-2.67 (m, 2H), 1.46-1.22 (m, 6H), 0.71 (s, 3H).

Example 193-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide

Synthesis of 3-Amino-6-(3-Fluoropyridin-2-yl)pyrazine-2-carboxylic Acid

Step 1. Synthesis of methyl3-amino-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxylate

A microwave vial equipped with a stirring bar was charged with methyl3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-carboxylate(515 mg, -80%, 1.847 mmol), PdCl₂(dppf)-DCM (81 mg, 0.099 mmol),2-bromo-3-fluoropyridine (250 mg, 1.421 mmol), cesium carbonate (741 mg,2.273 mmol) and dioxane (24 mL). Mixture was degassed for 5 minutes,then reaction was heated in a microwave reactor at 110° C. for 45minutes. After cooling to rt, the reaction mixture was filtered throughcelite, washed with EtOAc (35 mL) and concentrated under reducedpressure. The residue was then diluted with MeOH (25 mL) which led toprecipitation of a brown solid. Filtration of this solid gave 250 mg ofmethyl 3-amino-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxylate. LC-MS(Method 3, Basic): ret.time=0.84 min, M+H=249.0.

Step 2. Synthesis of3-amino-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxylic Acid

In a 40 ml vial methyl3-amino-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxylate (950 mg, 3.83mmol) was partially dissolved in methanol (5 mL). To this mixture LiOH(860 mg, 11.48 mmol) in water (0.5 mL) was added and the mixture stirredfor 3 h at room temperature. A solid precipitated during the reactionand was filtered which gave 1.13 g of3-amino-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxylic acid. LC-MS(Acidic method): ret.time=0.70 min, M+H=235.2.

Step 3: Synthesis of tert-butyl(1-(2-(3-amino-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate

To a solution of 3-amino-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxylicacid (500 mg, 2.135 mmol) in DCM/DMA (2:1, 4 ml/2 ml) was addedtert-butyl (1-(2-aminopyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(654 mg, 2.135 mmol), HBTU (1619 mg, 4.27 mmol) and DIPEA (1.492 mL,8.54 mmol). The reaction was stirred at rt for 16 h, then quenched withwater. The reaction was then diluted with DCM (25 mL) and washed withwater (15 mL) and brine (15 mL). The organic layer was then separated,dried over MgSO₄ and evaporated to give a brownish solid which was thenpurified via basic HPLC which afforded 424.5 mg of tert-butyl(1-(2-(3-amino-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate.LC-MS (Basic Method): ret.time=1.32 min, M+H=523.3.

4) Synthesis of3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide

In a 40 mL vial tert-butyl(1-(2-(3-amino-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate(424.5 mg, 0.812 mmol) was dissolved in DCM (2.5 ml). To this mixturewas added HCl/dioxane (2031 μL, 8.12 mmol) slowly. During the additionan orange solid was formed. The reaction was left to stir for 18 hbefore the precipitate was filtered. The obtained solid was then dilutedwith NaHCO₃(10 mL), and extracted with DCM (2×15 mL). The organic layerswere combined, dried over MgSO₄ and evaporated to give 170 mg of3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide.LC-MS (Basic method): ret.time=0.98 min, M+H=423.3. ¹H NMR (400 MHz,DMSO-d₆) δ 10.81 (s, 1H), 8.94 (s, 1H), 8.58 (dd, J=4.3, 1.8 Hz, 1H),8.11 (dd, J=4.8, 1.6 Hz, 2H), 7.90 (ddd, J=11.3, 8.4, 1.3 Hz, 2H),7.65-7.52 (m, 2H), 7.16 (dd, J=7.8, 4.8 Hz, 1H), 3.57 (s, 1H), 2.96 (td,J=11.0, 2.7 Hz, 2H), 2.74 (dt, J=11.6, 4.2 Hz, 2H), 1.50 (ddd, J=13.7,10.3, 3.8 Hz, 2H), 1.39-1.26 (m, 4H), 0.79 (s, 3H).

Example 203-amino-N-(3-((1R,5S,8s)-8-amino-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Step 1: Synthesis of tert-butyl((1R,5S,8s)-3-(2-nitropyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate

To a 25 mL pear shaped flask was added 3-fluoro-2-nitropyridine, (0.56g, 3.94 mmol), tert-butyl(1R,5S,8s)-3-azabicyclo[3.2.1]octan-8-ylcarbamate (0.849 g, 3.75 mmol),N-ethyl-N-isopropylpropan-2-amine, (1.11 g, 8.59 mmol) andtetrahydrofuran (14 mL) and a magnetic stirrer. The mixture was stirredunder nitrogen and heated at 70° C. for 1 day. The mixture was thencooled and concentrated to a thick residue and chromatographed directlyon silica gel (ethyl acetate-heptane) which gave tert-butyl ((1R,5S,8s)-3-(2-nitropyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate(0.993 g, 2.71 mmol) in 72% yield. LC-MS (Basic method): ret.time=1.41min, M+H=349.6.

Step 2: Synthesis of tert-butyl((1R,5S,8s)-3-(2-aminopyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate

To a 100 mL round bottom flask was added tert-butyl((1R,5S,8s)-3-(2-nitropyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate(0.99 g, 2.84 mmol), ethyl acetate (50 mL) and 10% palladium on carbonwet (1 g). The flask was purged with hydrogen and stirred under aballoon of hydrogen for 16 hrs. To the resultant mixture was then addedMgSO₄ (5 grams) and stirred. The mixture was then filtered through a padof MgSO₄ under a cone of nitrogen. The filtrate was concentrated todryness which gave tert-butyl((1R,5S,8s)-3-(2-aminopyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate(2.52 g, 1.322 mmol) in 98% yield. LC-MS (Basic method): ret.time=1.00min, M+H=319.5.

Step 3: Synthesis of tert-butyl((1R,5S,8s)-3-(2-(3-amino-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate

To a 10 mL screw cap vial was added3-amino-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylicacid (0.257 g, 0.696 mmol) which was prepared in analogy as in Example 1(Method 1), DMF (2.5 mL), N-ethyl-N-isopropylpropan-2-amine (0.334 g,0.2.58 mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (0.421 g, 1.107 mmol). The mixture was allowed tostir for 15 minutes. To the resultant mixture was added tert-butyl((1R,5S,8s)-3-(2-aminopyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate(0.235 g, 0.738 mmol) and allowed to stir for 18 hours. The reaction wasconcentrated and was purified by silica gel chromotography using ethylacetate and heptane which gave tert-butyl((1R,5S,8s)-3-(2-(3-amino-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate(0.494 g, 0.556 mmol) in 80% yield. LC-MS (Basic method): ret.time=1.28min, M+H=670.8.

Step 4: Synthesis of3-amino-N-(3-((1R,5S,8s)-8-amino-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

To a 100 mL flask was added a magnetic stirrer, tert-butyl((1R,5S,8s)-3-(2-(3-amino-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate(0.61 g, 0.923 mmol) and dichloromethane (10 mL). The mixture wasstirred until all solids dissolved and then cooled in an ice water bathunder nitrogen. To this mixture was added trifluoroacetic acid (25 mL).The ice bath was removed and the mixture was stirred for 2.5 hours atroom temperature. The mixture was then concentrated and the residue wasthen co-evaporated with toluene (30 mL) 3 times to a thick residue. Theresidue was purified by a reverse phase HPLC method which gave3-amino-N-(3-((1R,5S,8s)-8-amino-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide(0.084 g, 0.277 mmol) in 15% yield. LC-MS (Basic method): ret.time=1.12min, M+H=570.6. ¹H NMR (400 MHz, Chloroform-d) δ 10.48 (s, 3H), 8.56 (s,3H), 8.22 (d, J=4.8 Hz, 3H), 7.77 (d, J=9.0 Hz, 3H), 7.37 (d, J=7.9 Hz,3H), 6.99 (dd, J=8.0, 4.8 Hz, 3H), 6.58 (d, J=9.0 Hz, 3H), 3.90-3.67 (m,12H), 3.59 (t, J=4.8 Hz, 12H), 3.06-2.74 (m, 9H), 2.66 (d, J=10.7 Hz,6H), 1.83 (s, 6H), 1.20 (d, J=12.5 Hz, 16H).

Example 213-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoro-4-methoxypyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoro-4-methoxypyridin-2-yl)pyrazine-2-carboxamidewas prepared in a manner as described for Example 1, Method 1 (0.185 g)in 56% yield. LC-MS (Acidic method): ret.time=1.11 min, M+H=453.2

1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.91 (s, 1H), 8.41 (d, J=5.5Hz, 1H), 8.11 (dd, J=4.8, 1.6 Hz, 1H), 7.62 (dd, J=7.9, 1.7 Hz, 1H),7.33 (t, J=5.8 Hz, 1H), 7.16 (dd, J=7.8, 4.8 Hz, 1H), 3.97 (s, 3H), 2.95(dd, J=12.2, 9.5 Hz, 2H), 2.82-2.66 (m, 2H), 1.53 (ddd, J=13.7, 10.4,3.9 Hz, 2H), 1.44-1.13 (m, 4H), 0.82 (s, 3H).

Example 223-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamidewas prepared in a similar manner as described for Example 1, Method 1(0.01 g) in 58% yield. LC-MS (basic method): ret.time=2.11 min,M+H=452.2. ¹H NMR (400 MHz, Methanol-d4) δ 8.91 (d, J=1.2 Hz, 1H), 8.57(dt, J=4.6, 1.5 Hz, 1H), 8.13 (dd, J=5.0, 1.6 Hz, 1H), 7.83 (ddd,J=10.9, 8.4, 1.3 Hz, 1H), 7.70 (dd, J=7.9, 1.6 Hz, 1H), 7.57 (ddd,J=8.3, 4.6, 3.8 Hz, 1H), 7.20 (dd, J=7.9, 4.9 Hz, 1H), 3.48 (q, J=7.0Hz, 7H), 3.23 (s, 19H), 3.06-2.84 (m, 6H), 1.66 (ddd, J=14.8, 11.1, 4.3Hz, 2H), 1.52 (dt, J=13.1, 3.0 Hz, 2H), 1.18 (t, J=7.0 Hz, 10H).

Example 233-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-cyano-3-fluoropyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-cyano-3-fluoropyridin-2-yl)pyrazine-2-carboxamidewas prepared in a similar manner as described for Example 7, Method 2(0.016 g) in 78% yield. LC-MS (Acidic method): ret.time=0.72 min,M+H=448.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.79 (s, 3 H) 1.29-1.38 (m, 2H) 1.39-1.52 (m, 2 H) 2.73 (d, J=11.80 Hz, 2 H) 2.96 (t, J=9.79 Hz, 2 H)3.17 (d, J=3.51 Hz, 3 H) 4.12 (d, J=4.27 Hz, 1 H) 7.17 (dd, J=7.78, 4.77Hz, 1 H) 7.62 (dd, J=7.78, 1.51 Hz, 1 H) 8.11 (dd, J=4.77, 1.51 Hz, 1 H)8.18-8.29 (m, 2 H) 8.93 (s, 1 H) 10.70 (s, 1 H).

Example 243-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyanopyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyanopyridin-2-yl)pyrazine-2-carboxamidewas prepared in a similar manner as described for Example 1, Method 1(0.109 g) in 69% yield. LC-MS (Basic method): ret.time=1.92 min,M+H=429.2.

¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 9.18 (s, 1H), 8.95 (dd,J=4.8, 1.7 Hz, 1H), 8.52 (dd, J=8.0, 1.7 Hz, 1H), 8.29 (s, 1H),8.26-8.15 (m, 5H), 7.87-7.60 (m, 3H), 7.35 (dd, J=7.9, 5.0 Hz, 1H),3.20-3.02 (m, 3H), 2.97-2.79 (m, 3H), 2.01-1.73 (m, 3H), 1.64 (ddd,J=13.5, 9.2, 4.1 Hz, 2H), 1.36 (s, 1H), 1.05 (s, 3H).

Example 253-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide was prepared in a similar manner asdescribed for Example 1, Method 1 (3.15 g) in 83% yield. LC-MS (Basicmethod): ret.time=1.02 min, M+H=503.2.

1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.84 (s, 1H), 8.76 (dd,J=4.7, 1.3 Hz, 1H), 8.16 (br s, 1H), 8.10 (dd, J=4.8, 1.6 Hz, 1H), 8.07(dt, J=8.4, 1.4 Hz, 1H), 7.96 (br s, 1H), 7.65 (dd, J=8.4, 4.6 Hz, 1H),7.59 (dd, J=7.9, 1.6 Hz, 1H), 7.16 (dd, J=7.8, 4.8 Hz, 1H), 2.95 (td,J=11.5, 2.9 Hz, 2H), 2.75-2.68 (m, 2H), 1.35-1.18 (m, 4H), 1.07 (s, 2H),0.81 (q, J=7.4 Hz, 2H), 0.56 (t, J=7.4 Hz, 3H).

Example 263-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamidewas prepared in a similar manner as described for Example 7, Method 2(0.018 g) in 49% yield. LC-MS (Acidic method): ret.time=0.69 min,M+H=460.2. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 0.92 (s, 4 H) 1.56 (d,J=13.05 Hz, 2 H) 1.65-1.80 (m, 2 H) 2.90-2.98 (m, 2 H) 2.98-3.07 (m, 2H) 4.13 (s, 3 H) 7.24 (dd, J=8.03, 5.02 Hz, 1 H) 7.31 (d, J=6.02 Hz, 1H) 7.71 (dd, J=7.91, 1.38 Hz, 1 H) 8.14 (dd, J=4.89, 1.38 Hz, 1 H) 8.74(d, J=6.02 Hz, 1 H) 9.11 (s, 1 H).

Example 273-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide was prepared in a similar manner asdescribed for Example 1, Method 1 (0.018 g) in 49% yield. LC-MS (Acidicmethod): ret.time=0.79 min, M+H=519.2.

1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.89 (s, 1H), 8.79 (dd,J=4.6, 1.3 Hz, 1H), 8.17 (s, 1H), 8.14-8.06 (m, 2H), 7.98 (s, 1H), 7.69(dd, J=8.3, 4.6 Hz, 1H), 7.59 (dd, J=8.0, 1.7 Hz, 1H), 7.16 (dd, J=7.9,4.8 Hz, 1H), 3.09 (s, 3H), 2.97 (d, J=11.6, 2.7 Hz, 2H), 2.73 (dt,J=11.4, 3.7 Hz, 2H), 2.61 (s, 2H), 1.37 (dt, J=11.9, 6.5 Hz, 3H),1.31-1.21 (m, 2H).

Example 283-amino-N-(3-(4-amino-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamidewas prepared in a similar manner as described for Example 1, Method 1(0.039 g) in 38% yield. LC-MS (Basic method): ret.time=0.96 min,M+H=503.2. ¹H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.95 (dd, J=4.9,1.5 Hz, 1H), 8.76 (s, 1H), 8.40 (dd, J=8.1, 1.5 Hz, 1H), 8.22-8.06 (m,2H), 7.97 (br s, 1H), 7.71 (dd, J=8.0, 4.8 Hz, 1H), 7.56 (dd, J=7.9, 1.7Hz, 1H), 7.16 (dd, J=7.9, 4.8 Hz, 1H), 4.77 (s, 1H), 3.29 (t, J=6.6 Hz,2H), 2.94-2.83 (m, 2H), 2.71-2.63 (m, 2H), 1.39 (s, 2H), 1.27-1.13 (m,4H), 0.92 (t, J=6.6 Hz, 2H).

Example 293-amino-N-(3-((1S,5R,8S)-8-amino-6-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

The 3-amino-N-(3-((1S,5R,8S)-8-amino-6-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamidewas prepared in a similar manner as described for Example 1 (0.069 g) in14% yield. LC-MS (basic method): ret.time=1.69 min, M+H=572.6. ¹H NMR(400 MHz, Chloroform-d) δ 10.35 (s, 1H), 8.64 (s, 1H), 8.22 (d, J=4.8Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.00 (dd,J=7.9, 4.8 Hz, 1H), 6.59 (d, J=9.0 Hz, 1H), 3.99 (d, J=8.3 Hz, 1H), 3.87(d, J=4.2 Hz, 1H), 3.85-3.67 (m, 4H), 3.69-3.54 (m, 4H), 3.29 (dd,J=8.2, 4.8 Hz, 1H), 3.21-2.93 (m, 3H), 2.81 (dd, J=27.2, 11.4 Hz, 2H).

Examples 30-85

Examples 30-85, prepared by the synthetic methods (Methods 1-6)disclosed above, are summarized in Table 1

TABLE 1 Synthetic MS Compound Name Structure Method (M + H) 303-amino-N-(3-(4-aminopiperidin- 1-yl)pyridin-2-yl)-6-(5,6,7,8-tetrahydroquinazolin-4-yl)pyrazine-2- carboxamide

Method 1 446.2 31 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(thieno[2,3-d]pyrimidin-4-yl)pyrazine-2-carboxamide

Method 3 448.2 32 3-amino-N-(3-(4-amino-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2- carboxamide

Method 1 453.2 33 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6- (dimethylamino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 516.2 34 3-amino-N-(3-((1R,5S,8s)-8-amino-3-azabicyclo[3.2.1]octan-3- yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 570.6 35 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-cyano-3-fluoropyridin-2-yl)pyrazine-2- carboxamide

Method 3 448.2 36 3-amino-N-(3-(4-amino-4-(2-methoxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine- 2-carboxamide

Method 1 517.2 37 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2- yl)pyrazine-2-carboxamide

Method 1 558.6 38 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-fluoroquinazolin-4-yl)pyrazine-2- carboxamide

Method 3 474.2 39 3-amion-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazine-2- carboxamide

Method 3 449.2 40 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3- morpholinophenyl)pyrazine-2-carboxamide

Method 2 474.4 41 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3,6- bis(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Method 1 527.2 42 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(5- morpholino-2-(trifluoromethyl)phenyl)pyrazine-2- carboxamide

Method 1 557.6 43 (±) 3-amino-N-(3-((cis)-4-amino-3-fluoropiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 493.9 44 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(2- morpholinopyrimidin-4-yl)pyrazine-2-carboxamide

Method 1 477.3 45 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2- (3,6-dihydro-2H-pyran-4-yl)-5-(trifluoromethyl)pyrimidin-4-yl)pyrazine- 2-carboxamide

Method 1 555.2 46 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-morpholinoquinazolin-4-yl)pyrazine-2- carboxamide

Method 3 541.3 47 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(1-methyl-1H-indazol- 4-yl)pyrazine-2-carboxamide

Method 3 444.5 48 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(7-fluoroisoquinolin-1-yl)pyrazine-2- carboxamide

Method 3 473.2 49 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2- yl)pyrazine-2-carboxamide

Method 1 409.2 50 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-morpholinopyridin- 2-yl)pyrazine-2-carboxamide

Method 1 476.6 51 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3- morpholinophenyl)pyrazine-2-carboxamide

Method 2 475.6 52 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(7-chloroisoquinolin-1-yl)pyrazine-2- carboxamide

Method 3 490.2 53 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-(azetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 514.5 54 3-amino-N-(3-((3S,4R)-4-amino-3-fluoropiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 493.2 55 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(2-(trifluoromethyl)-1H-indol-4-yl)pyrazine-2-carboxamide

Method 3 497.5 56 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(5-morpholino-2-(trifluoromethyl)phenyl)pyrazine-2- carboxamide

Method 1 543.6 57 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-(dimethylamino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 3 502.4 58 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2- (4,4-difluoropiperidin-1-yl)-5-fluoropyrimidin-4-yl)pyrazine-2- carboxamide

Method 3 543.3 59 3-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide

Method 1 437.2 60 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(5- fluoro-2-morpholinopyrimidin-4-yl)pyrazine-2-carboxamide

Method 3 509.3 61 3-amino-N-(3-(4-aminoopiperidin-1-yl)pyridin-2-yl)-6-(1-methyl-1H-indol-4- yl)pyrazine-2-carboxamide

Method 3 443.6 62 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(1H-indazol-4- yl)pyrazine-2-carboxamide

Method 3 430.4 63 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-cyano-3-(trifluoromethyl)pyridin-2- yl)pyrazine-2-carboxamide

Method 1 498.2 64 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-fluoro-2- morpholinoquinazolin-4-yl)pyrazine-2-carboxamide

Method 3 559.3 65 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(2-methyl-1H-indol-4- yl)pyrazine-2-carboxamide

Method 3 443.6 66 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 3 544.5 67 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-ethoxy-3-(trifluoromethyl)pyridin-2- yl)pyrazine-2-carboxamide

Method 1 517.2 68 4-(5-amino-6-((3-(4-amino-4-methylpiperidin-1-yl)pyridin-2- yl)carbamoyl)pyrazin-2-yl)-5-fluoropyrimidine-2-carboxamide

Method 3 466.3 69 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-cyano-5-(trifluoromethyl)pyrimidin-4- yl)pyrazine-2-carboxamide

Method 3 498.2 70 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-amino-5-chloropyrimidin-4-yl)pyrazine-2- carboxamide

Method 3 455.2 71 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(1H-indol-4- yl)pyrazine-2-carboxamide

Method 2 429.2 72 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3- morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide

Method 3 526.3 73 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-morpholino-5-(trifluoromethyl)phenyl)pyrazine-2- carboxamide

Method 3 543.2 74 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-chloro-3-(trifluoromethyl)pyridin-2- yl)pyrazine-2-carboxamide

Method 1 507.2 75 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2- carboxamide

Method 3 60.5 76 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(5-morpholino-2- (trifluoromethyl)phenyl)pyrazine-2-carboxamide

Method 1 543.5 77 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 544.4 78 3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3- morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide

Method 3 526.6

Example 793-amino-N-(3-(4-aminopiperidin-1-yl)-6-methylpyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide

Step 1: Synthesis of 6-methyl-2-nitropyridin-3-yltrifluoromethanesulfonate

To a solution of 3-hydroxy-6-methyl-2-nitropyridine (1.0 g, 6.5 mmol) inDCM (24 mL) at 0° C. under N2 was added triethylamine (1.35 mL, 9.73mmol) and followed by triflicanhydride (1.32 mL, 7.79 mmol). The mixturewas stirred for 1 hours at 0° C. and then quenched with water. Theorganic layer was separated, washed with water and dried over MgSO4.After filtration and concentration at reduced pressure, the crudemixture was purified by flash chromatography on silica gel columneluting with 0-70% EtOAc/Heptane to afford the desired product as yellowoil (1.8 g, 98% yield). LC-MS (Acidic Method): ret.time=1.21 min,M+H=287.0. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.81 (d, 2 H) 7.59 (d, 1 H)2.70 (s, 3 H).

Step 2. Synthesis of tert-butyl(1-(6-methyl-2-nitropyridin-3-yl)piperidin-4-yl)carbamate

A mixture of 6-methyl-2-nitropyridin-3-yl trifluoromethanesulfonate(0.70 g, 2.45 mmol), tert-butyl piperidin-4-ylcarbamate (1.23 g, 6.11mmol), and triethylamine (0.85 ml, 6.11 mmol) in acetonitrile (20 ml)was refluxed for 8 h. The reaction was cooled to room temperature andconcentration at reduced pressure. The crude mixture was quenched withwater and extracted with DCM. The crude organic layer was purified byflash chromatography on silica gel (0-100% EtOAc/Heptane) to affordquantitative yield of the desired product as yellow solid. LC-MS (AcidicMethod): ret.time=1.27 min, M+H=337.2.

Synthesis of3-amino-N-(3-(4-aminopiperidin-1-yl)-6-methylpyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-aminopiperidin-1-yl)-6-methylpyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamidewas prepared in a manner as described for Example 1, Method 1 (94 mg) in16% yield. LC-MS (acidic method): ret.time=0.66 min, M+H=489.3. ¹H NMR(400 MHz, Methanol-d₄) δ 8.85 (s, 1H), 8.73 (dd, J=4.7, 1.4 Hz, 1H),8.00 (dt, J=8.4, 1.4 Hz, 1H), 7.61 (dd, J=8.4, 4.7 Hz, 1H), 7.53 (d,J=8.1 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 3.05 (dt, J=12.4, 3.6 Hz, 2H),2.76-2.60 (m, 3H), 2.50 (s, 3H), 1.85-1.75 (m, 2H), 1.42-1.29 (m, 2H).

Example 803-amino-N-(3-(4-aminopiperidin-1-yl)-6-methylpyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-aminopiperidin-1-yl)-6-methylpyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamidewas prepared in a manner as described for Example 1, Method 1 (105 mg)in 18% yield. LC-MS (acidic method): ret.time=0.64 min, M+H=473.3. ¹HNMR (400 MHz, Methanol-d4) δ 8.92 (dd, J=4.8, 1.5 Hz, 1H), 8.74 (s, 1H),8.37 (dd, J=8.1, 1.5 Hz, 1H), 7.83-7.62 (m, 1H), 7.49 (d, J=8.0 Hz, 1H),7.03 (d, J=8.0 Hz, 1H), 3.31 (p, J=1.6 Hz, 1H), 2.97 (dt, J=12.4, 3.6Hz, 2H), 2.64 (td, J=11.5, 2.4 Hz, 2H), 2.55 (br s, 1H), 2.49 (s, 3H),1.70 (dq, J=15.0, 3.1 Hz, 2H), 1.37-0.98 (m, 2H).

Example 813-amino-N-(3-(4-amino-3-methoxypiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide

Step 1: Synthesis of benzyl7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate

To a solution of benzyl 5,6-dihydropyridine-1(2H)-carboxylate (3.8 g, 17mmol) in DCM (60 ml) at −15° C. was added 3-chlorobenzoperoxoic acid(4.7 g, 70% pure, 19 mmol). The mixture was stirred at room temperaturefor 12 h and then washed with sodium bicarbonate solution. The organiclayer was dried over sodium sulfate, filtered, and concentration atreduced pressure. The crude mixture was purified by flash chromatographyon silica gel (30% EtOAc/Heptane) to afford the desired product as acolorless oil. LC-MS (Acidic Method): ret.time=1.08 min, M+H=234.3.

Step 2. Synthesis of benzyl4-(bis(2,4-dimethoxybenzyl)amino)-3-hydroxypiperidine-1-carboxylate

A suspension of dried lithium bromide (5.2 g, 60 mmol) in acetonitrile(15 ml) was stirred at 60° C. until a clear solution was formed. Benzyl7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (8 g, 34 mmol) inacetonitrile (35 ml) was added, followed bybis(2,4-dimethoxybenzyl)amine (12 g, 38 mmol), and acetonitrile (50 ml).The mixture was stirred at 60° C. for 46 h. The reaction was cooled toroom temperature and concentration at reduced pressure. The crudemixture was quenched with water and extracted with DCM. Aqueous layerwas further extracted with DCM twice. The combined organic layer waspurified by flash chromatography on silica gel (0-100% EtOAc/Heptane) togive two products with same M+H 551.0. The desired product came outfirst as colorless oil. LC-MS (Acidic Method): ret.time=1.18 min,M+H=551.0.

Step 3. Synthesis of benzyl4-(bis(2,4-dimethoxybenzyl)amino)-3-methoxypiperidine-1-carboxylate

To a solution of benzyl4-(bis(2,4-dimethoxybenzyl)amino)-3-hydroxypiperidine-1-carboxylate (5.0g, 9.1 mmol) in THF (100 ml) was added sodium hydride (0.55 g, 60% pure,14 mmol) at 0° C. under nitrogen atmosphere. Iodomethane (2.1 ml, 33mmol) was added. The mixture was stirred at room temperature for 12 h.The crude mixture was quenched with saturated aqueous ammonium chlorideand extracted with EtOAc. Aqeuous layer was further extracted with EtOActwice. The combined organic layer was washed with brine and purified byflash chromatography on silica gel (0-50% EtOAc/Heptane) to give thedesired product. LC-MS (Acidic Method): ret.time=1.14 min, M+H=565.0.

Step 4. Synthesis ofN,N-bis(2,4-dimethoxybenzyl)-3-methoxypiperidin-4-amine

A mixture of benzyl4-(bis(2,4-dimethoxybenzyl)amino)-3-methoxypiperidine-1-carboxylate (4.8g, 8.4 mmol), palladium on carbon (0.45 g, 10% pure, 0.42 mmol) inethanol (100 ml) was stirred under hydrogen balloon for 2.5 h. Filteredand concentrated to give the desired product as colorless oil. It wasused in the next step without further purification. LC-MS (AcidicMethod): ret.time=0.68 min, M+H=431.3.

Synthesis of3-amino-N-(3-(4-amino-3-methoxypiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-3-methoxypiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamidewas prepared in a manner as described for Example 1, Method 1 (43 mg) in75% yield. LC-MS (acidic method): ret.time=0.71 min, M+H=505.3. ¹H NMR(400 MHz, Chloroform-d) δ 10.96 (s, 1H), 8.88 (s, 1H), 8.82 (dd, J=4.5,1.4 Hz, 1H), 8.34 (dd, J=4.9, 1.6 Hz, 1H), 7.81 (dt, J=8.3, 1.4 Hz, 1H),7.52-7.41 (m, 2H), 7.09 (dd, J=7.9, 4.8 Hz, 1H), 3.51 (s, 1H), 3.41(ddd, J=11.0, 4.5, 2.1 Hz, 1H), 3.22 (s, 3H), 3.14-2.94 (m, 2H), 2.70(td, J=12.0, 2.5 Hz, 1H), 2.56 (ddd, J=11.6, 9.1, 4.6 Hz, 1H), 2.41 (t,J=10.5 Hz, 1H), 1.90-1.79 (m, 1H).

Example 823-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoro-4-methylpyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoro-4-methylpyridin-2-yl)pyrazine-2-carboxamidewas prepared in a manner as described for Example 1, Method 1 (8.6 mg)in 7.5% yield. LC-MS (acidic method): ret.time=1.04 min, M+H=437.1

¹H NMR (400 MHz, Methanol-d4) δ 8.83 (d, J=1.3 Hz, 1H), 8.39 (d, J=4.8Hz, 1H), 8.12 (dd, J=5.0, 1.6 Hz, 1H), 7.68 (dd, J=7.9, 1.6 Hz, 1H),7.40 (td, J=5.2, 0.9 Hz, 1H), 7.18 (dd, J=7.9, 4.9 Hz, 1H), 3.10-2.77(m, 4H), 2.45 (d, J=1.9 Hz, 3H), 1.81-1.40 (m, 4H), 0.87 (s, 3H).

Example 833-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-ethoxy-3-fluoropyridin-2-yl)pyrazine-2-carboxamide

Step 1: Synthesis of 2-bromo-4-ethoxy-3-fluoropyridine

A mixture of 2-bromo-3-fluoropyridin-4-ol (0.20 g, 1.0 mmol), iodoethane(0.22 ml, 2.1 mmol), and potassium carbonate (0.29 g, 2.1 mmol) inacetone (7 mL) was refluxed for 4 h. The reaction mixture wasconcentration at reduced pressure and purified by flash chromatographyon silica gel column eluting with 0-100% EtOAc/Heptane to afford thedesired product as white solid (0.19 g, 83% yield). LC-MS (AcidicMethod): ret.time=1.07 min, M+H=221.6.

Synthesis of3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-ethoxy-3-fluoropyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-ethoxy-3-fluoropyridin-2-yl)pyrazine-2-carboxamidewas prepared in a manner as described for Example 1, Method 1 (57 mg) in91% yield. LC-MS (acidic method): ret.time=1.06 min, M+H=467.2

¹H NMR (400 MHz, Methanol-d4) δ 8.86 (d, J=0.8 Hz, 1H), 8.35 (d, J=5.5Hz, 1H), 8.12 (dd, J=4.9, 1.6 Hz, 1H), 7.70 (dd, J=7.9, 1.6 Hz, 1H),7.30-7.14 (m, 2H), 4.28 (q, J=7.0 Hz, 2H), 3.05-2.83 (m, 4H), 1.73 (ddd,J=13.2, 9.2, 3.9 Hz, 2H), 1.64-1.53 (m, 2H), 1.51 (t, J=7.0 Hz, 3H),0.98 (s, 3H).

Example 843-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(hydroxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Step 1: Synthesis of (2-chloro-3-(trifluoromethyl)pyridin-4-yl)methanol

To a solution of 2-chloro-3-(trifluromethyl)isonicotinaldehyde (0.97 g,4.6 mmol) in MeOH (10 mL) at 0° C. was added sodium borohydride (0.23 g,6.0 mmol). The mixture was stirred at room temperature for 20 minutes.It was then concentrated and partitioned between DCM and water. Theorganic layer was washed with brine, dried over magnesium sulfate,filtered, and concentrated to give a yellow solid. (0.91 g, 93% yield).LC-MS (Acidic Method): ret.time=0.90 min, M+H=212.0.

Synthesis of3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(hydroxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(hydroxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamidewas prepared in a manner as described for Example 7, method 3 (36 mg) in94% yield. LC-MS (acidic method): ret.time=0.62 min, M+H=503.1. ¹H NMR(400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.89 (d, J=5.1 Hz, 1H), 8.68 (s,1H), 8.10 (dd, J=4.8, 1.6 Hz, 1H), 7.90 (d, J=5.1 Hz, 1H), 7.57 (dd,J=7.9, 1.7 Hz, 1H), 7.14 (dd, J=7.9, 4.8 Hz, 1H), 4.79 (s, 2H),4.10-4.04 (br, 1H), 2.88 (ddd, J=12.4, 7.5, 5.2 Hz, 2H), 2.64 (dt,J=11.4, 4.5 Hz, 2H), 1.23-1.11 (m, 4H), 0.65 (s, 3H).

Example 853-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(methoxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Step 1: Synthesis of2-chloro-4-(methoxymethyl)-3-(trifluoromethyl)pyridine

To a solution of 2-chloro-3-(trifluromethyl)pyridin-4-yl)methanol (0.15mg, 0.69 mmol) in THF (5 mL) was added potassium tert-butoxide (0.10 g,0.89 mmol). The mixture was stirred at room temperature for 10 minutes.It was then added methyl iodide (0.22 ml, 3.4 mmol) and stirred at roomtemperature for 17 h. Added more potassium tert-butoxide (0.10 g, 0.89mmol) and stirred at room temperature for another 12 h. The mixture wasthen filtered and washed with EtOAc. The combined organic layer waspurified by flash chromatography on silica gel column eluting with 0-30%EtOAc/Heptane to afford the desired product as colorless oil (25 mg, 16%yield). LC-MS (Acidic Method): ret.time=1.16 min, M+H=226.0.

Synthesis of3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(methoxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

The3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(methoxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamidewas prepared in a manner as described for Example 7, method 3 (7.5 mg)in 13% yield. LC-MS (acidic method): ret.time=1.11 min, M+H=517.1. ¹HNMR (400 MHz, Methanol-d4) δ 8.84 (d, J=5.1 Hz, 1H), 8.61 (s, 1H), 8.11(dd, J=5.0, 1.6 Hz, 1H), 7.88 (dd, J=5.0, 1.1 Hz, 1H), 7.66 (dd, J=7.9,1.7 Hz, 1H), 7.16 (dd, J=7.9, 4.9 Hz, 1H), 4.80-4.74 (m, 2H), 3.56 (s,3H), 3.03-2.69 (m, 4H), 1.46-1.25 (m, 4H), 0.76 (s, 3H).

79 3-amino-N-(3-(4-aminopiperidin-1-yl)-6- methylpyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 489.3 80 3-amino-N-(3-(4-aminopiperidin-1-yl)-6-methylpyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 473.3 81 3-amino-N-(3-(4-amino-3-methoxypiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 505.3 82 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoro-4- methylpyridin-2-yl)pyrazine-2-carboxamide

Method 1 437.1 83 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-ethoxy-3-fluoropyridin-2-yl)pyrazine-2- carboxamide

Method 1 467.2 84 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4- (hydroxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 3 503.1 85 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4- (methoxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 3 517.1The following compounds can be prepared according to the syntheticmethods (Methods 1-6) described herein.

Synthetic MS Compound Name Structure Method (M + H)  863-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-cyano-3-fluoropyridin-2-yl)pyrazine-2-carboxamide

Method 3 448.1  87 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(2- methylmorpholino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 3 572.4  88 3-amino-N-(3-(4-amino-4-(ethoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2- yl)pyrazine-2-carboxamide

Method 1 517.3  89 3-amino-N-(3-(4-amino-4-(ethoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2- yl)pyrazine-2-carboxamide

Method 1 531.4  90 3-amino-N-(3-(4-amino-4-((difluoromethoxy)methyl)piperidin-1- yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 539.2  91 3-amino-N-(3-(4-amino-4-((difluoromethoxy)methyl)piperidin-1- yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 555.3  92 3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(1-morpholinoisoquinolin-3- yl)pyrazine-2-carboxamide

Method 1 556.2  93 3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2- yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 574.7  94 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-isopropoxypyridin-2-yl)pyrazine- 2-carboxamide

Method 3 488.2  95 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3- cyano-4-cyclopropoxypyridin-2-yl)pyrazine-2-carboxamide

Method 3 486.2  96 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(trifluoromethoxy)pyridin-2-yl)pyrazine-2- carboxamide

Method 3 489.2  97 3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2- yl)pyrazine-2-carboxamide

Method 1 474.7  98 3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-cyanopyridin-2-yl)pyrazine-2- carboxamide

Method 1 474.7  99 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-(trifluoromethoxy)pyridin-2- yl)pyrazine-2-carboxamide

Method 3 514.2 100 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-phenoxypyridin-2-yl)pyrazine-2- carboxamide

Method 3 523.0 101 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(5-methoxy-3-(trifluoromethyl)pyridin-2- yl)pyrazine-2-carboxamide

Method 1 503.2 102 3-amino-N-(3-(4-amino-3-fluoro-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 491.0 103 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3- hydroxyazetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 4 544.2 104 3-amino-N-(3-(4-amino-4-(cyanomethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2- yl)pyrazine-2-carboxamide

Method 2 514.1 105 3-amino-N-(3-(4-amino-4-(cyanomethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2- yl)pyrazine-2-carboxamide

Method 1 498.3 106 3-amino-N-(3-(4-amino-3-fluoro-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 507.2 107 (R)-3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3- methylmorpholino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 572.3 108 (S)-3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3- methylmorpholino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 1 572.3 109 6-(6-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)-3-(trifluoromethyl)pyridin-2-yl)-3-amino-N-(3-(4-amino-4-methylpiperidin-1- yl)pyridin-2-yl)pyrazine-2-carboxamide

Method 4 584.3 110 3-amino-N-(3-((3S,4R)-4-amino-3-fluoro-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2- yl)pyrazine-2-carboxamide

Method 1 507.2 111 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-ethoxypyridin-2-yl)pyrazine-2- carboxamide

Method 3 474.0 112 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3- isopropylmorpholino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 3 600.3 113 3-amino-N-(3-(4-amino-3-fluoro-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2- yl)pyrazine-2-carboxamide

Method 1 521.3 114 3-amino-N-(3-(4-amino-4-(cyanomethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2- yl)pyrazine-2-carboxamide

Method 1 485.3 115 (R)-3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-((1-hydroxypropan-2-yl)amino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 4 546.2 116 (S)-3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-((1-hydroxypropan-2-yl)amino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 4 546.2 117 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6- ((2-hydroxyethyl)amino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 4 532.2 118 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(2- hydroxyethoxy)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 4 533.2 119 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3- methoxyazetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide

Method 4 558.2

Example 110 Synthesis of tert-butyl(3-fluoro-4-methyl-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate(Intermediate)

Step 1. Synthesis of 3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-one

To a 100 mL round-bottom flask equipped with a magnetic stirrer and anitrogen inlet, was added dioxane (10 mL), DMF (6 mL),3-fluoropiperidin-4-one (550 mg, 3.58 mmol), 3-fluoro-2-nitropyridine(509 mg, 3.58 mmol) and diisopropylethylamine (1.876 ml, 10.74 mmol).The homogenous solution was stirred at 70° C. in an oil bath for 4hours. The mixture was then partitioned between ethyl acetate (20 mL)and water (20 mL), and the organic extracts were washed with water (10ml) twice and brine (10 ml), and then dried over Na₂SO₄. Afterevaporation of solvent, an amber oil was collected as crude product,3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-one. Carried this crudeproduct to the next step directly without further purification.

LC-MS (Acidic Method): ret.time=0.63 min, M+H=240.1

Step 2. Synthesis of (Z)-ethyl2-(3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-ylidene)acetate

To a 100 mL round-bottom flask equipped with a magnetic stirrer and anitrogen inlet, was added NaH (169 mg, 4.21 mmol) and THF (10 mL). Themixture was cooled to 0° C. and added ethyl2-(dimethoxyphosphoryl)acetate (827 mg, 4.21 mmol) dropwise. Thereaction was stirred at room temperature for 20 minutes then a solutionof 3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-one (840 mg, 3.51 mmol)in THF (5 mL) was added. The mixture was stirred at room temperature for3 hours and was quenched by addition of water (25 mL) at 0° C. Theaqueous mixture was extracted with ethyl acetate (2×50 mL). The organiclayer was washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude material was purified by silica gelchromatography using ethyl acetate-heptane (Rf˜0.5 at 50% of ethylacetate in heptane). (Z)-ethyl2-(3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-ylidene)acetate wasobtained as light yellow solid.

LC-MS (Acidic Method): ret.time=1.44 min, M+H=310.2

Step 3. Synthesis of ethyl2-(4-amino-3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-yl)acetate

(Z)-ethyl 2-(3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-ylidene)acetate(4.02 g, 13 mmol) was dissolved in 10 mL of 7N NH₃ in MeOH in a pressurevessel. The vessel was sealed and heated at 80° C. for 12 hours.Evaporated the solvents and then applied to silica gel chromatography(Rf˜0.4 at 5% MeOH (0.5% of NH₄OH) in DCM) to collect ethyl2-(4-amino-3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-yl)acetatewith >80% purity.

LC-MS (Acidic Method): ret.time=0.68 min, M+H=327.3

Step 4. Synthesis of ethyl2-(4-((tert-butoxycarbonyl)amino)-3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-yl)acetate

To a 100 mL flask was added a magnetic stirrer and ethyl2-(4-amino-3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-yl)acetate (3 g,9.19 mmol) and BOC Anhydride (2.006 g, 9.19 mmol) in THF (Volume: 33 mL,Ratio: 1.000), Water (Volume: 33.0 mL, Ratio: 1.000) and THF (Volume:8.0 mL, Ratio: 1.000). Added DIPEA (1.606 mL, 9.19 mmol). The mixturewas heated at 85° C. for 4 hours. The mixture cooled down to roomtemperature and yellow precipitate was observed. The mixture wasfiltered and the solid was rinsed with water. The solid was purified bysilica gel chromatography (Rf˜0.7 at 70% of ethyl acetate in heptane) tocollect ethyl2-(4-((tert-butoxycarbonyl)amino)-3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-yl)acetate.

LC-MS (Acidic Method): ret.time=1.51 min, M+H=427.2

Step 5. Synthesis of2-(4-((tert-butoxycarbonyl)amino)-3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-yl)aceticacid

To a 100 mL flask was added a magnetic stirrer and ethyl2-(4-((tert-butoxycarbonyl)amino)-3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-yl)acetate(2.4 g, 5.82 mmol) in MeOH (6 mL) and THF (3 mL). An aqueous solution of3M NaOH (9.7 mL) was added and the reaction was heated at 55° C. for 2hours. Diluted the reaction mixture with water (10 mL) and washed withEt₂O (20 mL). The aqueous layer was acidified with 1N HCl slowly to pH˜6and then extracted with ethyl acetate (2×50 mL); combine the ethylacetate layers dried over Na₂SO₄, filtered and concentrated down.Purified by silica gel chromatography (Rf˜0.3 at 70% of ethyl acetate inheptane) to collect2-(4-((tert-butoxycarbonyl)amino)-3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-yl)aceticacid as yellow solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J=4.3Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.51 (dd, J=8.2, 4.4 Hz, 1H), 5.02 (s,1H), 4.92 (s, 1H), 3.36 (dd, J=26.9, 16.7 Hz, 2H), 3.10 (dt, J=22.4,11.5 Hz, 2H), 2.91 (d, J=17.1 Hz, 2H), 1.89 (s, 1H), 1.46 (s, 9H), 0.87(s, 1H).

LC-MS (Acidic Method): ret.time=1.05 min, M−56+H=343.1

Step 6. Synthesis of tert-butyl(3-fluoro-4-methyl-1-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate

To the mixture of2-(4-((tert-butoxycarbonyl)amino)-3-fluoro-1-(2-nitropyridin-3-yl)piperidin-4-yl)aceticacid (1 g, 2.51 mmol) and HOTT (1.118 g, 3.01 mmol) in acetonitrile (15mL), added triethylamine (1.399 mL, 10.04 mmol) in THF (5 mL), isolatedthe reaction vial from light by aluminum foil. Added DMAP (0.031 g,0.251 mmol) and kept the reaction stirred at room temperature for 2hours. To the reaction mixture was added tert-dodecyl mercaptan (2.363mL, 10.04 mmol) in acetonitrile (5 mL) and the reaction was brought toreflux for 18 hrs. The reaction mixture was concentrated and dilutedwith water (50 mL) and extracted with ethyl acetate. Collected ethylacetate layer and dried over Na₂SO₄; filtered and evaporated. Purifiedby silica gel chromatography with DCM/MeOH (0-7%) to collected thedesired product as yellow solid with >50% purity.

LC-MS (Basic Method): ret.time=1.38 min, M+H=355.1

This intermediate was then used as described in Method 3.

Biological Activity

PIM Kinase Inhibition Activity

For comparison between certain PKC inhibitors of the present applicationand structurally comparable PIM kinase inhibitors, the activity of PIM2was measured using an in vitro Caliper kinase assay. Liquid handling andincubation steps were done on an Innovadyne Nanodrop Express equippedwith a robotic arm (Thermo CatX, Caliper Twister II) and an incubator(Liconic STX40, Thermo Cytomat 2C450). The 384 well microtiter assayplates were prepared by addition of 50 nl per well of compound solutionin 90% DMSO. The kinase reactions were started by stepwise addition of4.5 μl per well of peptide/ATP-solution (50 mM HEPES, pH 7.5, 1 mM DTT,0.02% Tween20, 0.02% BSA, 0.6% DMSO, 10 mM beta-glycerophosphate, and 10μM sodium orthovanadate, 1 mM MgCl2, 25 uM ATP, and 2 uM S6 peptide) and4.5 μl per well of enzyme solution (50 mM HEPES, pH 7.5, 1 mM DTT, 0.02%Tween20, 0.02% BSA, 0.6% DMSO, 10 mM beta-glycerophosphate, and 10 μMsodium orthovanadate, 1 mM MgCl2, and 0.6 nM PIM2 enzyme).

Kinase reactions were incubated at 30° C. for 60 minutes andsubsequently terminated by addition of 16 μl per well of stop solution(100 mM HEPES pH 7.5, 5% DMSO, 0.1% Caliper coating reagent, 10 mM EDTA,and 0.015% Brij35). Plates with terminated kinase reactions weretransferred to the Caliper LC3000 workstations for reading.Phosphorylated and unphosphorylated peptides were separated using theCaliper microfluidic mobility shift technology. Briefly, samples fromterminated kinase reactions were applied to the chip. Analytes aretransported through the chip by constant buffer flow and the migrationof the substrate peptide is monitored by the fluorescence signal of itslabel. Phosphorylated S6 peptide (product) and unphosphorylated S6peptide (substrate) are separated in an electric field by theircharge/mass ratio. Kinase activities were calculated from the amounts offormed phospho-peptide. IC50 values were determined from percentinhibition values at different compound concentrations by non-linearregression analysis.

Compounds of the foregoing examples were tested by the Pim2 kinase assayand found to exhibit an IC50 values as shown in Table 4. IC50, the halfmaximal inhibitory concentration, represents the concentration of a testcompound of the invention that is required for 50% inhibition of itstarget in vitro.

GSKbeta Assay

Types of GSK-3 assay used to test the selectivity/off target potentialcompounds of the invention with respect to PKC α/θ inhibition activityincludes the following: Type 1: The GSK-3 specific peptide used in thisassay was derived from the phosphorylation site of glycogen synthase andits sequence is: YRRAAVPPSPSLSRHSSPHQ(S)EDEEE (S) is pre-phosphorylatedas is glycogen synthase in vivo and the three consensus sites for GSK-3specific phosphorylation are underlined. The buffer used to make up theglycogen synthase peptide and [γ-³³P] ATP consisted of MOPS 25 mM, EDTA0.2 mM, magnesium acetate 10 mM, Tween-20 0.01% and mercaptoethanol 7.5mM at pH 7.00. The compounds were dissolved in dimethyl sulphoxide(DMSO) to a final concentration of 100 mM. Various concentrations weremade up in DMSO and mixed with the substrate (GSK-3 peptide) solution(to a final concentration 20 μM) described in the above section alongwith rabbit or human GSK-3α and GSK-3β (final concentration 0.5 μM/mLenzyme). The reactions were initiated with the addition of [γ-³³P] ATP(500 cpm/pmole) spiked into a mixture of ATP (final concentration of 10μM). After 30 minutes at room temperature the reaction was terminated bythe addition of 10 μL of H₃PO₄/O.OP/0 Tween-20 (2.5%). A volume (10 μL)of the mixture was spotted onto P-30 phosphocellulose paper (Wallac &Berthold, EG&G Instruments Ltd, Milton Keynes). The paper was washedfour times in H₃PO₄ (0.5%), 2 minutes for each wash, air dried and theradioactive phosphate incorporated into the synthetic glycogen synthasepeptide, which binds to the P-30 phosphocellulose paper, was counted ina Wallac microbeta scintillation counter. Analysis of Data: Values forIC₅₀ for each inhibitor were calculated by fitting a four-parameterlogistic curve to the model: cpm=lower+(upper-lower)/(1+(concentrationIC₅₀)^(slo e)).

Type 2: This protocol is based on the ability of the kinase tophosphorylate a biotinylated peptide, sequence of which derived from thephosphorylation site of glycogen synthase and its sequence is:Biot-KYRRAAVPPSPSLSRHSSPHQ(S)EDEEE. (S) is a pre-phosphorylated serineas is glycogen synthase in vivo and the three consensus sites for GSK-3specific phosphorylation are underlined. The phosphorylated biotinylatedpeptide is then captured onto streptavidin coated SPA beads (AmershamTechnology), where the signal from the ³³P is amplified via thescintillant contained in the beads. The kinase was assayed at aconcentration of 10 nM final in 25 mM MOPS buffer, pH 7.0 containing0.01/o Tween-20, 7.5 mM 2-mercaptoethanol, 10 mM magnesium acetate, and10 μM [γ-³³P]-ATP. After 60 minutes incubation at room temperature, thereaction was stopped by addition of 50 mM EDTA solution containing theStreptavidin coated SPA beads to give a final 0.5 mg of beads per assaywell in a 384 microtiter plate format. 10 mM stock solutions of thecompounds of the invention in 100% DMSO are generated as a first step inthe screening process. The second step involves the creation of doseresponse plates where these compounds are diluted across the plate wherethe final low and high concentrations are to be 0.008 and 10 μM final inthe kinase assay. The third step involves the creation of the assayplates. This is achieved by transferring the compounds from four 96 doseresponse plates to one 384 assay plate on the Robocon Robolab system.The fourth step is to perform the assay as described and count theresulting plates in the Trilux (Wallac 1450 microbeta liquidscintillation and luminescence counter). The final step is dataacquisition and analysis where IC₅₀ values are generated for eachcompound in duplicate by fitting a four parameter logistic curve to themodel·cpm==lower+(upper-lower)/(1+(concentration/IC₅₀)^(s)*^(o)P^(e)) ina batch manner. The most potent PKC compounds of the present inventionshow GSKbetaICs₅₀ values in the range of from between 100 to 100,000 nM.

In Vitro PKCα/θ Inhibition Activity

The compounds of formula I were tested for their activity on differentPKC isoforms according to a published method (D. Geiges et al. Biochem.Pharmacol. 1997; 53:865-875) The assay is performed in a 96-wellpolypropylene microtiterplate (Costar 3794) that has been previouslysiliconized with Sigmacote (Sigma SL-2). The reaction mixture (50 μL)contains 10 μL of the relevant PKC isozyme together with 25 μL of thePKC inhibitor compound and 15 μL of a mix solution that contains 200μg/mL protamine sulfate, 10 mM Mg(NO₃)₂, 10 μM ATP (Boehringer 519987)and 3750 Bq of ³³P-ATP (Hartmann Analytic SFC301, 110 TBq/mmol) in 20 mMTris-buffer pH 7.4+0.1% BSA. Incubation was performed for 15 minutes at32° C. in a microtiterplate shaking incubator (Biolabo ScientificInstruments). Reaction was stopped by adding 10 μl of 0.5 M Na₂EDTA, pH7.4. 50 μl of mixture are pipetted onto a pre-wetted phosphocellulosepaper (Whatmann 3698-915) under gentle pressure. Non-incorporated ATP iswashed away with 100 μL bi-dist H₂O. The paper is washed twice in 0.5%H₃PO₄ for 15 minutes followed by 5 minutes in EtOH. Thereafter the paperis dryed and placed in an omnifilter (Packard 6005219), and overlayedwith 10 μL/well of Microscint-O (Packard 6013611) before counting in aTopcount radioactivity counter (Packard). IC₅₀ measurement is performedon a routine basis by incubating a serial dilution of inhibitor atconcentrations ranging between 1-1000 μM according to the proceduresdescribed above. IC₅₀ values are calculated from the graph by sigmoidalcurve fitting.

2. Protein Kinase C α Assay

Human recombinant PKCα is used under the assay conditions as describedabove. In this assay, compounds of formula I inhibit PKC α with anIC₅₀≤1 μM. Compound of Examples 2, 9 75 and 76 inhibits PKCα in thisassay with an IC₅₀<10 nM.

3. Protein Kinase C θ Assay

Human recombinant PKCθ was obtained from Oxford Biomedical Research andis used under the assay conditions as described under Section A.1 above:compounds of formula I inhibit PKC α with an IC₅₀≤1 μM. Compound ofExamples 2, 9, 75 and 76 inhibits PKCθ in this assay with an IC₅₀<10 nM.

Cellular Assays

To assess the ability of compounds of the invention to inhibit PKCactivity in cellular assays, compounds were evaluated for their abilityto selectively inhibit the proliferation of 92.1 uveal melanoma cellsand TMD8 B cell lymphoma cells, relative to SK-MEL-28 cells. 92.1 uvealmelanoma cells are dependent on the expression of a mutant form of the Gprotein alpha subunit, GNAQ, which signals via PKC to enable growth andproliferation. TMD8 cells are dependent on the expression of a mutantform of CD79 which signals via PKC to enable growth and proliferation.SK-MEL-28 cells are dependent on the expression of a mutant form ofB-Raf which does not signal via PKC to enable growth and proliferation.Therefore PKC inhibitors are expected to have anti-proliferativeactivity against 92.1 and/or TMD8 cells but not SK-MEL-28 cells. 92.1cells (GNAQ mutant) were obtained from Martine Jager (Leiden UniversityMedical Center, 2300 RC Leiden, The Netherlands). SK-MEL-28 cells can beobtained from the American Type Culture Collection (ATCC). Cells weremaintained in RPMI 1640 media (Lonza) and 10% FBS (Lonza).

Proliferation Assay

For each cell line, the cell density may be adjusted to 40 000 cells/mland 50 ul (2000 cells) added per well of a 384 well assay plate. Testcompounds are re-suspended in DMSO at a concentration of 10 mM. A serialthree-fold dilution of each compound with DMSO was performed in 384-wellplates using the Janus Liquid Dispenser (PerkinElmer). 50 nL of eachcompound dilution was transferred to the assay plate containing cellsfor final assay concentrations of 10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.12μM, 0.041 μM, 0.014 μM, 0.0046 μM, 0.0015 μM, 0.00051 μM.

Cells may be incubated at 37 degrees celsius in a humidified environmentwith 5% carbon dioxide for 72 hours. ATPlite (Perkin Elmer) was preparedaccording to the manufacturer's instructions and 25 μL added to eachwell of the assay plate. Plates are incubated for 10 minutes and theluminescence detected on an EnVision Multimode plate reader (PerkinElmer). The degree of luminescence correlates with the number of viablecells in each well. The effect of each inhibitor concentration wascalculated and IC₅₀ values can be generated.

The PKCisoform alpha and theta IC₅₀ values for PKC inhibitors (Examples1-29) are summarized in Table 2. The data presented herein representsthe average of at least two replicates

TABLE 2 Selected PKC α/θ inhibition IC₅₀ data for Examples 1-29. PKC PKCAlpha Theta Compound (nM) (nM) 13-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3- 1.3 2.8(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 23-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3- 0.25 1.3(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 33-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-7.4 1.3 (3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 43-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3 0.13 0.3morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide 53-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-5.9 2 (3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 63-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-0.22 2.1 (3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 73-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-morpholino-3-0.13 0.27 (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 83-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(2-morpholino 1 16thiazol-4-yl)pyrazine-2-carboxamide 93-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3- 1.9 0.4(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 103-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3- 0.9 2.8(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 113-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2- 0.3 3.1morpholino-5-(trifluoromethyl)pyrimidin-4-yl)pyrazine-2-carboxamide 123-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-fluoro-0.9 1.8 2-methylquinazolin-4-yl)pyrazine-2-carboxamide 133-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4- 1.30.45 methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 143-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3,3-0.68 1.2difluoroazetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 153-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6- 0.4 2.1cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 163-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6- 0.630.69 methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 173-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3- 2.1 1.1(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 18 Synthesis of3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)- 0.7 0.96-(3-chloropyridin-2-yl)pyrazine-2-carboxamide 193-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3- 1.7 3.6fluoropyridin-2-yl)pyrazine-2-carboxamide 203-amino-N-(3-((1R,5S,8s)-8-amino-3-azabicyclo[3.2.1]octan-3-yl)pyridin-0.5 3.62-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 213-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoro-0.55 1.2 4-methoxypyridin-2-yl)pyrazine-2-carboxamide 223-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-0.86 1.2 (3-fluoropyridin-2-yl)pyrazine-2-carboxamide 233-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-cyano-1.9 3.9 3-fluoropyridin-2-yl)pyrazine-2-carboxamide 243-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3- 0.4 1.2cyanopyridin-2-yl)pyrazine-2-carboxamide 253-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3- 0.6 2.1(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 263-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano- 14.7 4-methoxypyridin-2-yl)pyrazine-2-carboxamide 273-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-3.4 12 (3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 283-amino-N-(3-(4-amino-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-6-1.9 1.3 (3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 293-amino-N-(3-((1S,5R,8S)-8-amino-6-oxa-3-azabicyclo[3.2.1]octan-3- 0.246 yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

The PKCisoform alpha and theta IC₅₀ values for PKC inhibitors (Examples30-123) are summarized in Table 3

TABLE 3 Selected PKC α/θ inhibition IC₅₀ data for Examples 30-119. PKCPKC Alpha Theta Ex. Compound (nM) (nM) 303-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(5,6,7,8- 0.43 7.9tetrahydroquinazolin-4-yl)pyrazine-2-carboxamide 313-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(thieno[2,3-d]pyrimidin-0.84 7.4 4-yl)pyrazine-2-carboxamide 323-amino-N-(3-(4-amino-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-0.88 4 6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide 333-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6- 0.553.8(dimethylamino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide34 3-amino-N-(3-((1R,5S,8s)-8-amino-3-azabicyclo[3.2.1]octan-3- 0.50 3.6yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 353-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4- 0.993.4 cyano-3-fluoropyridin-2-yl)pyrazine-2-carboxamide 363-amino-N-(3-(4-amino-4-(2-methoxyethyl) piperidin-1-yl)pyridin-2- 9.329 yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 373-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6- 0.572.9 morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 383-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6- 1.5 2.9fluoroquinazolin-4-yl)pyrazine-2-carboxamide 393-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(5-fluoro-7H- 0.332.9 pyrrolo[2,3-d]pyrimidin-4-yl)pyrazine-2-carboxamide 403-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3- 0.13 2.8morpholinophenyl)pyrazine-2-carboxamide 413-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3,6- 0.46 2.7bis(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 423-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(5- 0.172.7 morpholino-2-(trifluoromethyl)phenyl)pyrazine-2-carboxamide 43 (±)3-amino-N-(3-((cis)-4-amino-3-fluoropiperidin-1-yl)pyridin-2-yl)-6- 0.302.2 (3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 443-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(2- 0.29 2.2morpholinopyrimidin-4-yl)pyrazine-2-carboxamide 453-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-(3,6-0.13 2.1 dihydro-2H-pyran-4-yl)-5-(trifluoromethyl)pyrimidin-4-yl)pyrazine-2- carboxamide 463-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2- 0.131.7 morpholinoquinazolin-4-yl)pyrazine-2-carboxamide 473-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(1-methyl-1H- 0.271.6 indazol-4-yl)pyrazine-2-carboxamide 483-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(7- 2.3 1.5fluoroisoquinolin-1-yl)pyrazine-2-carboxamide 493-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-0.33 1.5 2-yl)pyrazine-2-carboxamide 503-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6- 0.19 1.5morpholinopyridin-2-yl)pyrazine-2-carboxamide 513-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3- 0.20 1.5morpholinophenyl)pyrazine-2-carboxamide 523-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(7- 1.8 1.3chloroisoquinolin-1-yl)pyrazine-2-carboxamide 533-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-(azetidin-1-yl)-0.20 1.3 3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 543-amino-N-(3-((3S,4R)-4-amino-3-fluoropiperidin-1-yl)pyridin-2-yl)-6-0.25 1.2 (3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 553-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(2- 0.13 0.99(trifiuoromethyl)-1H-indol-4-yl)pyrazine-2-carboxamide 563-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(5-morpholino-2-0.13 0.88 (trifluoromethyl)phenyl)pyrazine-2-carboxamide 573-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6- 0.13 0.87(dimethylamino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide58 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2-(4,4-0.13 0.85difluoropiperidin-1-yl)-5-fluoropyrimidin-4-yl)pyrazine-2-carboxamide 593-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3- 0.860.71 fluoropyridin-2-yl)pyrazine-2-carboxamide 603-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(5- 0.140.68 fluoro-2-morpholinopyrimidin-4-yl)pyrazine-2-carboxamide 613-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(1-methyl-1H- 0.130.68 indol-4-yl)pyrazine-2-carboxamide 623-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(1H-indazol-4- 0.130.67 yl)pyrazine-2-carboxamide 633-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4- 0.80.63 cyano-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 643-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-fluoro-2- 0.130.43 morpholinoquinazolin-4-yl)pyrazine-2-carboxamide 653-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(2-methyl-1H- 0.130.36 indol-4-yl)pyrazine-2-carboxamide 663-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-morpholino-3-0.13 0.36 (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 673-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4- 1.30.33 ethoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 684-(5-amino-6-((3-(4-amino-4-methylpiperidin-1-yl)pyridin-2- 0.4 0.27yl)carbamoyl)pyrazin-2-yl)-5-fluoropyrimidine-2-carboxamide 693-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2- 0.481.9 cyano-5-(trifluoromethyl)pyrimidin-4-yl)pyrazine-2-carboxamide 703-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(2- 0.350.24 amino-5-chloropyrimidin-4-yl)pyrazine-2-carboxamide 713-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(1H-indol-4- 0.130.23 yl)pyrazine-2-carboxamide 723-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3- 0.13 0.2morpholinoisoquinolin-1-yl)pyrazine-2-carboxamide 733-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-morpholino-5-0.13 0.16 (trifluoromethyl)phenyl)pyrazine-2-carboxamide 743-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4- 0.50.13 chloro-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 753-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3- 0.97 4.7(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 763-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3- 0.130.88 cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide 773-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(5-morpholino-2-0.13 0.36 (trifluoromethyl)phenyl)pyrazine-2-carboxamide 783-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(6-morpholino-3-0.13 0.2 (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 793-amino-N-(3-(4-aminopiperidin-1-yl)-6-methylpyridin-2-yl)-6-(3- 4.9 26(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 803-amino-N-(3-(4-aminopiperidin-1-yl)-6-methylpyridin-2-yl)-6-(3- 32 51(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 81 (±)3-amino-N-(3-(trans 4-amino-3-methoxypiperidin-1-yl)pyridin-2-yl)-6-(3-0.36 19 (trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 823-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoro-4-4.9 4.6 methylpyridin-2-yl)pyrazine-2-carboxamide 833-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-ethoxy-3-1.1 5.3 fluoropyridin-2-yl)pyrazine-2-carboxamide 843-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4- 19 2.9(hydroxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide85 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4- 132.6(methoxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide863-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-cyano-3-1.9 3.9 fluoropyridin-2-yl)pyrazine-2-carboxamide 873-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(2- 0.512methylmorpholino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide883-amino-N-(3-(4-amino-4-(ethoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-6.3 0.79 (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 893-amino-N-(3-(4-amino-4-(ethoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-0.16 0.29 (trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 903-amino-N-(3-(4-amino-4-((difluoromethoxy)methyl)piperidin-1-yl)pyridin-2-11 3.6 yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 913-amino-N-(3-(4-amino-4-((difluoromethoxy)methyl)piperidin-1-yl)pyridin-2-4.2 15 yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 923-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(1-0.25 3.1 morpholinoisoquinolin-3-yl)pyrazine-2-carboxamide 933-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(6-0.13 0.13morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 943-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-1.8 0.86 isopropoxypyridin-2-yl)pyrazine-2-carboxamide 953-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-1 32 cyclopropoxypyridin-2-yl)pyrazine-2-carboxamide 963-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4- N/A N/A(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 973-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-1.3 8.6 cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide 983-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-0.85 3.6 cyanopyridin-2-yl)pyrazine-2-carboxamide 993-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-0.6 1.8 (trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 1003-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-23 100 phenoxypyridin-2-yl)pyrazine-2-carboxamide 1013-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(5-methoxy-3-5.1 6.6 (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 1023-amino-N-(3-(4-amino-3-fluoro-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-37 14 (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 1033-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3- 5.229hydroxyazetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide1043-amino-N-(3-(4-amino-4-(cyanomethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-4.4 66 (trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 1053-amino-N-(3-(4-amino-4-(cyanomethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-12 27 (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 1063-amino-N-(3-(4-amino-3-fluoro-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-2.7 57 (trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 107(R)-3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3-0.89 7.7methylmorpholino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide108(S)-3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3-0.32 3.8methylmorpholino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide1096-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(trifluoromethyl)pyridin-2-yl)-3-0.94 4.8amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)pyrazine-2-carboxamide1103-amino-N-(3-((3S,4R)-4-amino-3-fluoro-4-methylpiperidin-1-yl)pyridin-2-yl)-14 66 6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide 1113-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-3.6 16 ethoxypyridin-2-yl)pyrazine-2-carboxamide 1123-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3- N/AN/Aisopropylmorpholino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide1133-amino-N-(3-(4-amino-3-fluoro-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-21 30 yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide 1143-amino-N-(3-(4-amino-4-(cyanomethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-0.53 4.1 cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide 115(R)-3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-((1-0.26 3.9hydroxypropan-2-yl)amino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide116(S)-3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-((1-2 18hydroxypropan-2-yl)amino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide117 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-((2-0.84 2hydroxyethyl)amino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide118 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(2-2.3 28hydroxyethoxy)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide119 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(6-(3-4.8 21methoxyazetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Table 4 presents comparative PKCα/θ inhibition activity data as well asother kinase activity data for Example 1, a PKC inhibitor from thisapplication, and various PIM kinase inhibitors

TABLE 4 Selected kinase IC₅₀ data comparison between a PIM kinaseinhibitor and various PKC inhibitors SKMEL PKCα PKCθ GSK3β PIM 2 92.1Cell Cell Compound (nM) (nM) (nM) (nM) (nM) (nM)

50 590 97 490 6,150 >10,000

0.13 0.33 0.1 1.4 116 143

0.15 0.25 1 770 361 1860

0.13 0.84 0.2 10 370 190

0.19 1.5 0.2 13 680 975

0.8 6 0.2 78 360 140

1.3 2.8 5,500 >10,000 141 >10,000Table 4 presents a direct comparison of the kinase assay data forvarious PIM kinase inhibitors disclosed in WO2008/160692 and Example 1,an exemplary PKC inhibitor disclosed in this application. These datareveal that Example 1 is unexpectedly selective with regards to offtarget GSK3β and unexpectedly potent in suppressing 92.1 (uvealmelanoma) cell proliferation, as compared to the exemplary PIMinhibitors. This increased selectivity is likely the result of thepyridin-3-yl hinge portion attached to the piperdin-4-yl moiety which ispresent in Example 1. The pyridine-3-yl hinge portion is found in all ofthe PKC inhibitor compounds of this application. None of the exemplaryPIM kinase inhibitors in Table 4 posess the pyridin-3-yl hinge portionand as shown in Table 4 the PIM kinase inhibitors are relativelynon-selective. Accordingly, structurally similar PIM kinase inhibitorsdisclosed in WO2008/160692 do not or would not be expected to have theselectivity of the PKC inhibitors disclosed herein. In addition, thedata in Table 4 shows that Example 1 has little to no PIM2 activity,which further differentiates the PKC inhibitor compounds of thisapplication from known PIM kinase inhibitors.

Representative on target and off target kinase IC₅₀ data for additionalexemplary PKC inhibitors of the invention are summarized in Table 5

TABLE 5 Kinase Inhibition IC₅₀ data for PKC inhibitors of the presentapplication. Ex. PKC Alpha (nM) PKCtheta (nM) GSK3 Beta (nM) TMD8 Cell(nM) 92.1 Cell (nM) SKMEL Cell (nM) 1 1.3 2.8 5500 ND 141 >10,000 2 0.251.3 2,400 245 110 >10,000 4 0.13 0.3 3,100 147 71 >10,000 6 0.22 2.11,300 151 261 >10,000 8 1 16 210 240 40 3860 9 1.9 0.4 3,100 900184 >10,000 10 0.9 2.8 2,100 385 228 >10,000 13 1.3 0.45 2,100 76367 >10,000 20 0.5 3.6 10,000 410 387 >10,000 21 0.25 1.2 2,100 17612 >10,000 30 0.6 2.1 1,500 227 188 >10,000 75 0.97 4.7 2,400 146108 >10,000 76 0.13 0.88 6,500 77 34 >10,000 77 0.13 0.36 >10,000 72 144430 78 0.13 0.2 3,400 41 22 7015In Vivo Efficacy Models—92.1 Uveal Melanoma Xenograft Studies ofSelected PKC Inhibitors

Mice were implanted with 92.1 GNAQ mutant uveal melanoma cells to testthe in vivo efficacy of PKC inhibitors. Each mouse was injectedsubcutaneously (axillary region) with 5×10⁶ cells mixed in 50 LlMatrigel and 50 uL PBS. Tumor growth was monitored until tumors reacheda volume of 150-250 mm³ Tumor size, in mm³, was calculated from: TumorVolume=(w²×1)/2 where w=width and l=length, in mm, of the tumor. Whentumors reached the required size, test compounds were administered withthe required doses and schedules at a dosing volume of 10 ml/kg. Animalswere weighed twice per week and dosing volumes adjusted accordingly.Tumor volume was measured twice a week using caliper measurements andtumor volumes calculated as Length×width²/2. The in-vivo data wasgenerated for certain potent and selective PKC inhibitors (Examples 2,9) and compared with AEB071. The invented PKC inhibitors achieved tumorregression as compared to tumor statsis for AEB071 at doses lower thanthose for AEB071 that only achieved stasis in the model.

Example 2 decreases tumor proliferation in a 92.1 uveal melanomaxenografts in a dose dependent manner, as compared to sotrastaurin (FIG.1). Further, Example 2 shows a significant reduction in dose to achieveimproved efficacy (regression) vs. sotrastaurin (stasis). Based on thedata presented herein the compounds disclosed in this application eitherdo or would be expected to selectively induce tumor regression in auveal melanoma model harboring GNAQ mutations, as well as achieveimproved efficacy (regression) vs. sotrastaurin (stasis), as shown inFIG. 1. For example, as seen in FIG. 3, Example 9 and Example 10 alsoshow improved efficacy (regression) in a 92.1 uveal melanoma xenograftmodel as compared to vehicle. Accordingly it is expected that thecompounds disclosed herein do or would be expected to selectively inducetumor regression in vivo.

A comparison of in-vivo mouse and rat pharmacokinetic data for Example 2and sotrastaurin (Tables 6 and 7) shows that Example 2 has improved PKversus sotrastaurin.

TABLE 6 In vivo Mouse Pharmacokinetic Data Comparison (C57BL/6) Dose IV:1 mg/kg PO: 10 mg/kg Example 2 AEB071 CL (ml/min · kg) 14 28 Vss (l/kg)0.4 1.9 t_(1/2) (h) 0.5 1.2 AUC (nmol · h/l) i.v. 2455 1209 AUC (nmol ·h/l) p.o. 1377 2151 C_(max) (nM) p.o. 946 688 T_(max) p.o. (h) 0.3 1.7Oral BA (% F) 6 19

TABLE 7 In vivo Rat Pharmacokinetic Data Comparison (Non-cannulatedWistar-Han) Dose 0.3 mg/kg PO: 3 mg/kg Example 2 AEB071 CL (ml/min · kg)28 18 Vss (l/kg) 1.1 2.3 t_(1/2) (h) 0.7 1.7 AUC (nmol · h/l) i.v. 380609 AUC (nmol · h/l) p.o. 2765 620 C_(max) (nM) p.o. 756 158 T_(max)p.o. (h) 1.5 0.5 Oral BA (% F) 72 10

The compounds of this application represent an improved class ofselective, small molecule PKC inhibitors with proven in-vivo anti-tumoractivity and selectivity as compared to sotrastaurin. Moreover the PKCinhibitors of the this application generally exhibit improved potency,PK profile, absorption, gastrointestinal tolerance and kinaseselectivity as compared to known PKC inhibitors.

The invention claimed is:
 1. A method for treating a cancer selectedfrom melanoma, uveal melanoma, lymphoma, diffused large B-cell lymphoma,ibrutinib resistant cancers and non-small cell lung cancer in a humansubject in recognized need of such treatment, comprising administeringto the subject a therapeutically effective daily dose of from 0.001 to1000 mg/kg of subject body weight of a compound formula II:

or a pharmaceutically acceptable salt thereof, wherein: X is N or CR; R,R², R³ and R⁴ are each independently H, ²H, halo, hydroxy (—OH), C₁₋₃alkoxy, C₁₋₃ haloalkyl or C₁₋₃ alkyl, said C₁₋₃ alkyl optionallysubstituted with hydroxyl, halo, C₁₋₃ alkoxy or C₁₋₃ haloalkoxy; R⁵ isindependently H, ²H, CH₃, CH₂F, CHF₂, CF₃, CH₂OH, or C₁₋₃ alkyl, saidC₁₋₃ alkyl optionally substituted with F, OH, C₁₋₃ alkoxy or C₁₋₃haloalkoxy; R^(5a) and R^(5b) are each independently H, ²H, C₁₋₃ alkyl,said C₁₋₃ alkyl optionally substituted with F, OH or C₁₋₃ alkoxy, orR^(5a) and R^(5b) are joined together forming a methylene or ethylenebridging group; R^(5c) and R^(5d) are each independently H, ²H, F, —OH,C₁₋₃ alkoxy, C₁₋₃ alkyl, said C₁₋₃ alkyl optionally substituted with F,OH or C₁₋₃ alkoxy, or R^(5c) and R^(5d) are joined together forming amethylene, ethylene or —CH₂—O— bridging group; R⁶, R⁷ and R⁸ are eachindependently selected from H, ²H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, C₃₋₇ cycloalkyl and 4-7 memberedheterocyclyl having 1 to 3 heteroatoms selected from N, O and S, saidC₁₋₃ alkyl optionally substituted with F, OH, C₁₋₃ alkoxy or C₁₋₃haloalkoxy.
 2. The method according to claim 1 wherein the cancer isnon-small cell lung cancer.
 3. The method according to claim 2, whereinthe compound of formula II is selected from:3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-chloropyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoro-4-methoxypyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyanopyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-cyano-3-fluoropyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(2-methoxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;(+)3-amino-N-(3-((cis)-4-amino-3-fluoropiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-((3S,4R)-4-amino-3-fluoropiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-ethylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-cyano-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-ethoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-chloro-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-aminopiperidin-1-yl)-6-methylpyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-aminopiperidin-1-yl)-6-methylpyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-3-methoxypiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-fluoro-4-methylpyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-ethoxy-3-fluoropyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(hydroxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;and3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(methoxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;or a pharmaceutically acceptable salt thereof.
 4. The method accordingto claim 2, wherein the compound of formula II is selected from:3-amino-N-(3-(4-amino-4-(ethoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(ethoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-((difluoromethoxy)methyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-isopropoxypyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-cyclopropoxypyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-cyanopyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-phenoxypyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(5-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-3-fluoro-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(cyanomethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(cyanomethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-3-fluoro-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-((3S,4R)-4-amino-3-fluoro-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-ethoxypyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-3-fluoro-4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;and3-amino-N-(3-(4-amino-4-(cyanomethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide;or a pharmaceutically acceptable salt thereof.
 5. The method accordingto claim 2, wherein the compound of formula II is selected from:3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-aminopiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide;and3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide;or a pharmaceutically acceptable salt thereof.
 6. The method accordingto claim 2, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 7. The method accordingto claim 2, wherein the compound of formula (II) is:

or a pharmaceutically acceptable salt thereof.
 8. The method accordingto claim 2, wherein the compound or pharmaceutically acceptable saltthereof is administered in combination with at least one additionalanticancer agent.
 9. The method according to claim 7, wherein thecompound or pharmaceutically acceptable salt thereof is administered incombination with at least one additional anticancer agent.
 10. Themethod according to claim 8 wherein the anticancer agent is an EGFRinhibitor.
 11. The method according to claim 9 wherein the anticanceragent is an EGFR inhibitor.
 12. The method according to claim 10 whereinthe EGFR inhibitor is gefitinib or erlotinib.
 13. The method accordingto claim 11 wherein the EGFR inhibitor is gefitinib or erlotinib. 14.The method of claim 1 wherein the compound of formula (II) is a PKCinhibitor that is pan active to conventional and novel PKC isoforms. 15.The method of claim 2 wherein the compound of formula (II) is a PKCinhibitor that is pan active to conventional and novel PKC isoforms. 16.The method of claim 7 wherein the compound of formula (II) is a PKCinhibitor that is pan active to conventional and novel PKC isoforms. 17.The method of claim 8 wherein the compound of formula (II) is a PKCinhibitor that is pan active to conventional and novel PKC isoforms. 18.The method claim 9 wherein the compound of formula (II) is a PKCinhibitor that is pan active to conventional and novel PKC isoforms. 19.The method claim 10 wherein the compound of formula (II) is a PKCinhibitor that is pan active to conventional and novel PKC isoforms. 20.The method claim 11 wherein the compound of formula (II) is a PKCinhibitor that is pan active to conventional and novel PKC isoforms. 21.The method claim 12 wherein the compound of formula (II) is a PKCinhibitor that is pan active to conventional and novel PKC isoforms. 22.The method claim 13 wherein the compound of formula (II) is a PKCinhibitor that is pan active to conventional and novel PKC isoforms. 23.The method of claim 1 wherein the daily dose is administered as multipledivided doses.